Removable tip for laser device with safety interlock

ABSTRACT

The present invention provides an improved method of removing fluids, gases or other biomolecules, or delivering a pharmaceutical composition, through the skin of a patient without the use of a sharp or needle. The method includes the step of irradiating the stratum corneum, an applied pharmaceutical or an absorbing material, using a laser. By selection of parameters, the laser irradiates the selected material or tissue to create pressure gradients, plasma, cavitation bubbles, or other forms of tissue ablation or alteration. These methods increase the diffusion of pharmaceuticals into, or fluids, gases or other biomolecules out of, the body. For this invention, a pharmaceutical composition can be applied to the skin before or after laser irradiation.

[0001] This application is a continuation-in-part of pending U.S. Ser.No. 08/792,335, filed Jan. 31, 1997, said application is incorporatedherein by reference.

FIELD OF THE INVENTION

[0002] This invention is in the field of medical procedures, namelylaser medical equipment used in the delivery of anesthetics orpharmaceuticals to, or the removal of fluids, gases or otherbiomolecules from, a patient.

BACKGROUND

[0003] The traditional method for the collection of small quantities offluids, gases or other biomolecules from a patient utilizes mechanicalperforation of the skin with a sharp device such as a metal lancet orneedle. Additionally, the typical method of administering anesthetics orother pharmaceuticals is through the use of a needle.

[0004] These procedures have many drawbacks, including the possibleinfection of health care workers and the public by the sharp device usedto perforate the skin, as well as the cost of handling and disposal ofbiologically hazardous waste.

[0005] When skin is perforated with a sharp device such as a metallancet or needle, biological waste is created in the form of the “sharp”contaminated by the patient's blood and/or tissue. If the patient isinfected with blood-born agents, such as human immunodeficiency virus(HIV), hepatitis virus, or the etiological agent of any other diseases,the contaminated sharp poses a serious threat to others that might comein contact with it. For example, many medical workers have contractedHIV as a result of accidental contact with a contaminated sharp.

[0006] Post-use disposal of contaminated sharps imposes both logisticaland financial burdens on the end user. These costs are imposed as aresult of the social consequences of improper disposal. For example, inthe 1980's improperly disposed biological wastes washed up on publicbeaches on numerous occasions. Improper disposal also permits others,such as intravenous drug users, to obtain contaminated needles andspread disease.

[0007] There exists an additional drawback of the traditional method ofusing a needle for administering anesthetics or pharmaceuticals, as wellas for drawing fluids, gases or other biomolecules. The pain associatedwith being stabbed by a the sharp instrument can be a traumatizingprocedure, especially in pediatric patients, causing significant stressand anxiety in the patient. Moreover, for drawing fluids, gases or otherbiomolecules the stabbing procedure often must be repeated beforesufficient fluid is obtained.

[0008] The current technology for applying local anesthetic without theuse of needles typically involves either (a) topical lidocaine mixtures,(b) iontophoresis, (c) carriers or vehicles which are compounds thatmodify the chemical properties of either the stratum corneum, or thepharmaceutical, and (d) sonophoresis which involves modifying thebarrier function of stratum corneum by ultrasound. A cream containinglidocaine is commonly used, especially in pediatric patients, but needsto be applied for up to 60 minutes, and anesthesia is produced to adepth of only about 4 mm. The lack of lidocaine penetration is aconsequence of the barrier function of the stratum corneum. Inherentproblems with iontophoresis include the complexity of the deliverysystem, cost, and unknown toxicology of prolonged exposure to electricalcurrent. Additionally, the use of carriers or vehicles involvesadditional compounds which might modify the pharmacokinetics of thepharmaceutical of interest or are irritating.

[0009] Thus, a need exists for a technique to remove fluids, gases orother biomolecules or to administer anesthetics or other pharmaceuticalswhich does not require a sharp instrument. The method and apparatusdisclosed herein fulfill this need and obviate the need for the disposalof contaminated instruments, thereby reducing the risk of infection.

[0010] Lasers have been used in recent years as a very efficient precisetool in a variety of surgical procedures. Among potentially new sourcesof laser radiation, the rare-earth elements are of major interest formedicine. One of the most promising of these is a YAG (yttrium,aluminum, garnet) crystal doped with erbium (Er) ions. With the use ofthis crystal, it is possible to build an erbium-YAG (Er:YAG) laser whichcan be configured to emit electromagnetic energy at a wavelength (2.94microns) which is strongly absorbed by, among other things, water. Whentissue, which consists mostly of water, is irradiated with radiation ator near this wavelength, energy is transferred to the tissue. If theintensity of the radiation is sufficient, rapid heating can resultfollowed by vaporization of tissue. In addition, deposition of thisenergy can result in photomechanical disruption of tissue. Some medicaluses of Er:YAG lasers have been described in the health-care disciplinesof dentistry, gynecology and ophthalmology. See, e.g., Bogdasarov, B.V., et al., “The Effect of Er:YAG Laser Radiation on Solid and SoftTissues,” Preprint 266, Institute of General Physics, Moscow, 1987;Bol'shakov, E. N. et al., “Experimental Grounds for Er:YAG LaserApplication to Dentistry,” SPIE 1353:160-169, Lasers and Medicine (1989)(these and all other references cited herein are expressly incorporatedby reference as if fully set forth in their entirety herein).

SUMMARY OF THE INVENTION

[0011] The present invention employs a laser to perforate or alter theskin of a patient so as to remove fluids, gases or other biomolecules orto administer anesthetics or other pharmaceuticals. Perforation oralteration is produced by irradiating the surface of the target tissuewith a pulse or pulses of electromagnetic energy from a laser. Prior totreatment, the care giver properly selects the wavelength, energyfluence (energy of the pulse divided by the area irradiated), pulsetemporal width and irradiation spot size so as to precisely perforate oralter the target tissue to a select depth and eliminate undesired damageto healthy proximal tissue.

[0012] According to one embodiment of the present invention, a laseremits a pulsed laser beam, focused to a small spot for the purpose ofperforating or altering the target tissue. By adjusting the output ofthe laser, the laser operator can control the depth, width and length ofthe perforation or alteration as needed.

[0013] In another embodiment continuous-wave or diode lasers may be usedto duplicate the effect of a pulsed laser beam. These lasers aremodulated by gating their output, or, in the case of a diode laser, byfluctuating the laser excitation current in a diode laser. The overalleffect is to achieve brief irradiation, or a series of briefirradiations, that produce the same tissue permeating effect as a pulsedlaser. The term “modulated laser” is used herein to indicate thisduplication of a pulsed laser beam.

[0014] The term, “perforation” is used herein to indicate the ablationof the stratum corneum to reduce or eliminate its barrier function. Theterm, “alteration” of the stratum corneum is used herein to indicate achange in the stratum corneum which reduces or eliminates the barrierfunction of the stratum corneum and increases permeability withoutablating, or by merely partially ablating, the stratum corneum itself. Apulse or pulses of infrared laser radiation at a subablative energy of,e.g., 60 mJ (using a TRANSMEDICA™ International, Inc. (“TRANSMEDICA™”)Er:YAG laser with a beam of radiant energy with a wavelength of 2.94microns, a 200 μs (microsecond) pulse, and a 2 mm spot size) will alterthe stratum corneum. The technique may be used for transdermal drugdelivery or for obtaining samples, fluids, gases or other biomolecules,from the body. Different wavelengths of laser radiation and energylevels less than or greater than 60 mJ may also produce the enhancedpermeability effects without ablating the skin.

[0015] The mechanism for this alteration of the stratum corneum is notcertain. It may involve changes in lipid or protein nature or functionor be due to desiccation of the skin or mechanical alterations secondaryto propagating pressure waves or cavitation bubbles. The pathway thattopically applied drugs take through the stratum corneum is generallythought to be through cells and/or around them, as well as through hairfollicles. The impermeability of skin to topically applied drugs isdependent on tight cell to cell junctions, as well as the biomolecularmakeup of the cell membranes and the intercellular milieu. Any changesto either the molecules that make up the cell membranes or intercellularmilieu, or changes to the mechanical structural integrity of the stratumcorneum and/or hair follicles can result in reduced barrier function. Itis believed that irradiation of the skin with radiant energy produced bythe Er:YAG laser causes measurable changes in the thermal properties, asevidenced by changes in the Differential Scanning Calorimeter (DSC)spectra as well as the Fourier Transform Infrared (FTIR) spectra of thestratum corneum. Changes in DSC and FTIR spectra occur as a consequenceof changes in molecules or macromolecular structure, or the environmentaround these molecules or structures. Without wishing to be bound to anyparticular theory, we can tentatively attribute these observations tochanges in lipids, water and protein molecules in the stratum corneumcaused by irradiation of molecules with electromagnetic radiation, bothby directly changing molecules as well as by the production of heat andpressure waves which can also change molecules.

[0016] Both perforation and alteration change the permeabilityparameters of the skin in a manner which allows for increased passage ofpharmaceuticals, as well as fluids, gases or other biomolecules, acrossthe stratum corneum.

[0017] Accordingly, one object of the present invention is to provide ameans for perforating or altering the stratum corneum of a patient in amanner that does not result in bleeding. For example, the perforation oralteration created at the target tissue is accomplished by applying alaser beam that penetrates through the stratum corneum layer or both thestratum corneum layer and the epidermis, thereby reducing or eliminatingthe barrier function of the stratum corneum. This procedure allows theadministration of anesthetics or other pharmaceuticals, as well as theremoval of fluids, gases or other biomolecules, through the skin.Moreover, this procedure allows drugs to be administered continually onan outpatient basis over long periods of time. The speed and/orefficiency of drug delivery is thereby enhanced for drugs which wereeither slow or unable to penetrate skin.

[0018] In another embodiment of this invention, pressure waves, plasma,and cavitation bubbles are created in or above the stratum corneum toincrease the permeation of the compounds (e.g., pharmaceuticals) orfluid, gas or other biomolecule removal. This method may simply overcomethe barrier function of intact stratum corneum without significantalteration or may be used to increase permeation or collection inablated or altered stratum corneum. As described herein, pressure waves,plasma, and cavitation bubbles are produced by irradiating the surfaceof the target tissue, or material on the target tissue, with a pulse orpulses of electromagnetic energy from a laser. Prior to treatment, thecare giver properly selects the wavelength, energy fluence (energy ofthe pulse divided by the area irradiated), pulse temporal width andirradiation spot size to create the pressure waves, plasma, orcavitation bubbles while limiting undesired damage to healthy proximaltissue.

[0019] A further object of this invention is to provide an alternativemeans for administering drugs that would otherwise be required to betaken through other means, such as orally or injected, therebyincreasing patient compliance and decreasing patient discomfort.

[0020] An additional object of this invention is to allow the taking ofmeasurements of various fluid constituents, such as glucose, or toconduct measurements of gases.

[0021] A further object of this invention is to avoid the use of sharps.The absence of a contaminated sharp will eliminate the risk ofaccidental injury and its attendant risks to health care workers,patients, and others that may come into contact with the sharp. Theabsence of a sharp in turn obviates the need for disposal ofbiologically hazardous waste. Thus, the present invention provides anecologically sound method for administering anesthetics or otherpharmaceuticals, as well as removing fluids, gases or otherbiomolecules.

[0022] In another embodiment a typical laser is modified to include acontainer unit. Such a container unit can be added to: (1) increase theefficiency in the collection of fluids, gases or other biomolecules; (2)reduce the noise created when the laser beam perforates the patient'stissue; and (3) collect the ablated tissue. The optional container unitis alternatively evacuated to expedite the collection of the releasedmaterials such as the fluids, gases or other biomolecules. The containercan also be used to collect only ablated tissue. The noise created fromthe laser beam's interaction with the patient's skin may cause thepatient anxiety. The optional container unit reduces the noise intensityand therefore alleviates the patient's anxiety and stress. The containerunit also minimizes the risk of cross-contamination and guarantees thesterility of the collected sample. The placement of the container unitin the use of this invention is unique in that it covers the tissuebeing irradiated, at the time of irradiation by the laser beam, and istherefore able to collect the fluid, gas or other biomolecule samplesand/or ablated tissue as the perforation or alteration occurs. Thecontainer unit may also be modified for the purpose of containingmaterials, such as drugs, which may be applied before, simultaneously orshortly after irradiation.

[0023] A typical laser used for this invention requires no specialskills to use. It can be small, light-weight and can be used withregular or rechargeable batteries. The greater the laser's portabilityand ease of use, the greater the utility of this invention in a varietyof settings, such as a hospital room, clinic, or home.

[0024] Safety features can be incorporated into the laser that requirethat no special safety eyewear be worn by the operator of the laser, thepatient, or anyone else in the vicinity of the laser when it is beingused.

BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The present invention may be better understood and its advantagesappreciated by those skilled in the art by referring to the accompanyingdrawings wherein:

[0026]FIG. 1 shows a laser with its power source, high voltagepulse-forming network, flashlamp, lasing rod, mirrors, housing andfocusing lens.

[0027]FIG. 2 shows an optional spring-loaded interlock and optionallyheated applicator.

[0028]FIG. 3 shows an alternative means of exciting a laser rod using adiode laser.

[0029]FIG. 4 shows an alternative focusing mechanism.

[0030]FIGS. 5A & 5B show optional beam splatters for creating multiplesimultaneous perforations.

[0031]FIG. 6 shows a patch that can be used to sterilize the site ofirradiation.

[0032]FIGS. 7A & 7B show alternative patches for sterilization and/ordelivery of pharmaceuticals, and/or collection of fluids, gases or otherbiomolecules.

[0033]FIG. 8 shows an optional container unit for collecting fluids,gases or other biomolecules, ablated tissue, and/or other matterreleased from the site of irradiation, and for reducing noise resultingfrom the interaction between the laser and the patient's tissue.

[0034]FIG. 9 shows a plug and plug perforation center.

[0035]FIG. 10 shows an optional container unit for collecting ablatedtissue and reducing noise resulting from the interaction between thelaser and the patient's tissue.

[0036]FIG. 11 shows a roll-on device for the delivery of anesthetics orpharmaceuticals.

[0037]FIG. 12 shows an elastomeric mount for a solid state laser crystalelement with optional mirrored surfaces applied to each end of theelement.

[0038]FIG. 13 shows an example of a crystal rod with matte finish aroundthe full circumference of the entire rod.

[0039]FIG. 14 shows an example of a crystal rod with matte finish aroundthe full circumference of two-thirds of the rod.

[0040]FIG. 15 shows an example of a crystal rod with matte stripes alongits longitudinal axis.

[0041]FIG. 16 shows a cross-section of a crystal laser rod elementsurrounded by a material having an index of refraction greater than theindex of refraction of the rod.

[0042] FIGS. 17A-17G show various examples of a container unit.

[0043]FIG. 18 shows an atomizer for the delivery of anesthetics orpharmaceuticals.

[0044]FIG. 19 shows examples of a container unit in use with a laser.

[0045]FIG. 20 shows an example of a lens with a mask.

[0046]FIG. 21 is a chart showing a study using corticosterone whichshowed enhanced permeation (over controls) at an energies of 77 mJ and117 mJ.

[0047]FIG. 22 shows the decrease in the impedance of skin in vivo usingvarious laser pulse energies.

[0048] FIGS. 23-24 show in a permeation study of tritiated water(³H₂O)involving lased human skin at energies from 50 mJ (1.6 J/cm²) to 1250 mJ(40 J/cm²).

[0049]FIG. 25 shows histological sections of human skin irradiated atenergies of 50 mJ and 80 mJ.

[0050]FIG. 26 is a chart of a study using DNA showing enhancedpermeation through skin irradiated at an energy of 150 mJ and 300 mJ.

[0051]FIG. 27 shows laser pulse energy (J) versus water loss throughhuman skin in vivo.

[0052]FIG. 28 is a chart showing a DSC scan of normally hydrated (66%)human stratum corneum, and a scan of Er:YAG laser irradiated stratumcorneum using a subablative pulse energy of 60 mJ.

[0053] FIGS. 29-31 are charts showing the heat of transition (μJ),center of the transition (° C.) and the full-width at half-maximum ofthe transition (° C.) of three peaks in the DSC spectra for stratumcorneum treated different ways.

[0054] FIGS. 32-33 are charts of FTIR spectra of control and lasedstratum corneum.

[0055]FIG. 34 shows Amide I band position (cm⁻¹) as a function ofstratum corneum treatment.

[0056]FIG. 35 shows CH₂ vibration position (cm⁻¹) as a function ofstratum corneum treatment.

[0057]FIG. 36 shows a histological section of rat skin that wasirradiated at 80 mJ.

[0058]FIG. 37 shows a histological section of human skin that wasirradiated at 80

[0059]FIG. 38 shows in vivo blanching assay results.

[0060]FIG. 39-41 shows permeation of γ-interferon, insulin andlidocaine, through human skin in vitro.

[0061]FIG. 42 shows an example of a beam splitter suitable for makingsimultaneous irradiation sites.

[0062]FIG. 43 shows one possible pattern of perforation or alterationsites using a beam splitter.

[0063]FIG. 44 shows a pressure gradient created in the stratum corneum.

[0064]FIG. 45 is a schematic of modulating the pulse repetitionfrequency of radiant energy from high (4 GHz) to low (4 MHz).

[0065]FIG. 46 shows a propagating pressure wave created in an absorbingmaterial located on the skin.

[0066]FIG. 47 shows a propagating pressure wave created at the skinsurface with a transparent, or partially transparent, optic located onthe skin.

[0067]FIG. 48 shows a propagating pressure wave created in an absorbingmaterial on the applied pharmaceutical.

[0068]FIG. 49 shows a propagating pressure wave created in the appliedpharmaceutical.

[0069]FIG. 50 shows the creation of pressure waves in tissue convergingto a focal point.

DETAILED DESCRIPTION

[0070] This invention provides a method for perforating or altering skinfor either the sampling of fluids, gases or other biomolecules or theadministration of anesthetics or other pharmaceuticals. The inventionutilizes a laser beam, specifically focused, and lasing at anappropriate wavelength, to create small perforations or alterations inthe skin of a patient. In a preferred embodiment, the laser beam has awavelength between about 0.2 and 10 microns. More preferably, thewavelength is between about 1.5 and 3.0 microns. Most preferably thewavelength is about 2.94 microns. In one embodiment, the laser beam isfocused with a lens to produce an irradiated spot on the skin with asize of approximately 0.5 microns-5.0 cm diameter. Optionally, the spotcan be slit-shaped, with a width of about 0.05-0.5 mm and a length of upto 2.5 mm.

[0071] The caregiver may consider several factors in defining the laserbeam, including wavelength, energy fluence, pulse temporal width andirradiation spot-size. In a preferred embodiment, the energy fluence isin the range of 0.03-100,000 J/cm². More preferably, the energy fluenceis in the range of 0.03-9.6 J/cm². The beam wavelength is dependent inpart on the laser material, such as Er:YAG. The pulse temporal width isa consequence of the pulse width produced by, for example, a bank ofcapacitors, the flashlamp, and the laser rod material. The pulse widthis optimally between 1 fs (femtosecond) and 1,000 μs.

[0072] According to the method of the present invention the perforationor alteration produced by the laser need not be produced with a singlepulse from the laser. In a preferred embodiment the caregiver produces aperforation or alteration through the stratum corneum by using multiplelaser pulses, each of which perforates or alters only a fraction of thetarget tissue thickness.

[0073] To this end, one can roughly estimate the energy required toperforate or alter the stratum corneum with multiple pulses by takingthe energy in a single pulse, and dividing by the number of pulsesdesirable. For example, if a spot of a particular size requires 1 J ofenergy to produce a perforation or alteration through the entire stratumcorneum, then one can produce a qualitatively similar perforation oralteration using ten pulses, each having {fraction (1/10)}th the energy.Because it is desirable that the patient not move the target tissueduring the irradiation (human reaction times are on the order of 100 msor so), and that the heat produced during each pulse not significantlydiffuse, in a preferred embodiment the pulse repetition rate from thelaser should be such that complete perforation is produced in a time ofless than 100 ms. Alternatively, the orientation of the target tissueand the laser can be mechanically fixed so that changes in the targetlocation do not occur during the longer irradiation time.

[0074] To penetrate the skin in a manner which does not induce much ifany blood flow, skin is perforated or altered through the outer surface,such as the stratum corneum layer, but not as deep as the capillarylayer. The laser beam is focussed precisely on the skin, creating a beamdiameter at the skin in the range of 0.5 microns-5.0 cm. The width canbe of any size, being controlled by the anatomy of the area irradiatedand the desired permeation rate of the pharmaceutical to be applied, orfluid, gas or other biomolecule to be removed. The focal length of thefocussing lens can be of any length, but in one embodiment it is 30 mm.

[0075] By modifying wavelength, pulse length, energy fluence (which is afunction of the laser energy output (in Joules) and size of the beam atthe focal point (cm²)), and irradiation spot size, it is possible tovary the effect on the stratum corneum between ablation (perforation)and non-ablation or partial ablation (alteration). Both ablation andnon-ablative alternation of the stratum corneum result in enhancedpermeation of subsequently applied pharmaceuticals, or removal offluids, gases or other biomolecules.

[0076] For example, by reducing the pulse energy while holding othervariables constant, it is possible to change between ablative andnon-ablative tissue-effect. Using the TRANSMEDICA™ Er:YAG laser, whichhas a pulse length of about 300 μs, with a single pulse or radiantenergy and irradiating a 2 mm spot on the skin, a pulse energy aboveapproximately 100 mJ causes ablation, while any pulse energy belowapproximately 100 mJ causes non-ablative alteration to the stratumcorneum. Optionally, by using multiple pulses, the threshold pulseenergy required to enhance pharmaceutical delivery is reduced by afactor approximately equal to the number of pulses.

[0077] Alternatively, by reducing the spot size while holding othervariables constant, it is also possible to change between ablative andnon-ablative tissue-effect. For example, halving the spot area willresult in halving the energy required to produce the same effect.Irradiations down to 0.5 microns can be obtained, for example, bycoupling the radiant output of the laser into the objective lens of amicroscope objective (e.g. as available from Nikon, Inc., Melville,N.Y.). In such a case, it is possible to focus the beam down to spots onthe order of the limit of resolution of the microscope, which is perhapson the order of about 0.5 microns. In fact, if the beam profile isGaussian, the size of the affected irradiated area can be less than themeasured beam size and can exceed the imaging resolution of themicroscope. To non-ablatively alter tissue in this case, it would besuitable to use a 3.2 J/cm² energy fluence, which for a half-micron spotsize, would require a pulse energy of about 5 nJ. This low a pulseenergy is readily available from diode lasers, and can also be obtainedfrom, for example, the Er:YAG laser by attenuating the beam with anabsorbing filter, such as glass.

[0078] Optionally, by changing the wavelength of radiant energy whileholding the other variables constant, it is possible to change betweenan ablative and non-ablative tissue-effect. For example, using Ho:YAG(holmium: YAG; 2.127 microns) in place of the Er:YAG (erbium: YAG; 2.94microns) laser, would result in less absorption of energy by the tissue,creating less of a perforation or alteration.

[0079] Picosecond and femtosecond pulses produced by lasers can also beused to produce alteration or ablation in skin. This can be accomplishedwith modulated diode or related microchip lasers, which deliver singlepulses with temporal widths in the 1 femtosecond to 1 ms range. (See D.Stern et al., “Corneal Ablation by Nanosecond, Picosecond, andFemtosecond Lasers at 532 and 625 nm,” Corneal Laser Ablation, vol. 107,pp. 587-592 (1989), incorporated herein by reference, which disclosesthe use of pulse lengths down to 1 femtosecond).

[0080] According to one embodiment of the present invention, theanesthetic or pharmaceutical can be administered immediately after laserirradiation. Two embodiments of this invention incorporate an atomizer(FIG. 18) or a roll-on device (FIG. 11). In the case of a roll-ondevice, the laser beam propagates through hole 162 incorporated in ball164 of the roll-on device. In the alternative, the roll-on device can bepositioned adjacent to the path of the laser beam through the disposableapplicator. After irradiation, the roll-on device is rolled over theirradiated site, thereby administering the desired anesthetic orpharmaceutical. In the case of an atomizer, the anesthetic isadministered from a drug reservoir 166 through the use of compressedgas. After irradiation, a cylinder 168 containing compressed gas (suchas, for example, carbon dioxide) is triggered to spray a set amount ofanesthetic or pharmaceutical over the irradiated site.

[0081] Alternatively, it would be beneficial to apply positive pressureto a drug reservoir thereby pushing the drug into the skin, or negativepressure in a collection reservoir thus enhancing the diffusion ofanalytes out of the skin. Ambient atmospheric pressure is 760 mm Hg, or1 atmosphere. Because of hydrostatic pressure in a standing individual,the relative pressure difference in the head may be 10 mm Hg below areference value taken at the level of the neck, and 90 mm Hg higher inthe feet. The arms may be between 8 and 35 mm Hg. Note also that becauseof the beating heart, a dynamic pressure (in a normal, healthyindividual) of between 80-120 mm Hg is in the circulation. Thus, topermeate a drug through the skin (say in the arm), a positive pressureof greater than about 760 mm+35 mm Hg would be suitable. A pressure justslightly over 1 atmosphere would be suitable to enhance drug permeation,and yet would not enhance diffusion into the blood stream because of thedynamic pressures in the blood stream. A higher pressure mightbeneficially enhance diffusion into the blood stream. However, extendedpressures much greater than perhaps 5 or so atmospheres for extendedtimes might actually produce side effects.

[0082] In another embodiment of the present invention, an ink jet ormark is used for marking the site of irradiation. The irradiated sitesare often not easily visible to the eye, consequently the health careprovider may not know exactly where to apply the anesthetic orpharmaceutical subsequent to laser irradiation. This invention furtherprovides techniques to mark the skin so that the irradiation site isapparent. For example, an ink-jet (analogous to those used in ink-jetprinters) can be engaged prior to, during or immediately after laserirradiation. Additionally, a circle can be marked around the ablationsite, or a series of lines all pointing inward to the ablation site canbe used. Alternatively, the disposable safety-tip/applicator can bemarked on the end (the end that touches up against the skin of thepatient) with a pigment. Engaging the skin against the applicator priorto, during, or immediately after lasing results in a mark on the skin atthe site of irradiation.

[0083] For certain purposes, it is useful to create multipleperforations or alterations of the skin simultaneously or in rapidsequence. To accomplish this, a beam-splitter can optionally be added tothe laser, or a rapidly pulsing laser, such as a diode or relatedmicrochip lasers, may be used. Multiple irradiated sites, createdsimultaneously or sequentially, would result in an increased uptake ofdrugs as compared to a single irradiation site (i.e. an increase inuptake proportional to the total number of ablated sites). An example ofa beam splitter 48 suitable for making simultaneous irradiation sitesfor use with a laser can be found in FIG. 42. Any geometric pattern ofspots can be produced on the skin using this technique. Because thediffusion into skin of topically applied drugs can be approximated assymmetric, a beneficial pattern of irradiation spots for local drugdelivery (such that a uniform local concentration would result over aswide an area as possible) would be to position each spot equidistantfrom each other in a staggered matrix pattern (FIG. 43).

[0084] Alternatively, multiple irradiation sites, or an irradiated areaof arbitrary size and shape, could be produced with use of a scanner.For example, oscillating mirrors which reflect the beam of laser radiantenergy can operate as a scanner.

[0085] For application of the laser device for anesthetic orpharmaceutical delivery, as well as fluid, gas or other biomoleculeremoval, the laser is manipulated in such a way that a portion of thepatient's skin is positioned at the site of the laser focus within theapplicator. For perforations or alterations for the delivery ofanesthetics and other pharmaceuticals, as well as fluid, gas or otherbiomolecule removal, a region of the skin which has less contact withhard objects or with sources of contamination is preferred, but notrequired. Examples are skin on the arm, leg, abdomen or back.Optionally, the skin heating element is activated at this time in orderto reduce the laser energy required for altering or ablating the stratumcorneum.

[0086] Preferably a holder is provided with a hole coincident with thefocal plane of the optical system. Optionally, as shown in FIG. 2, aspring-loaded interlock 36 can be attached to the holder, so that whenthe patient applies a small amount of pressure to the interlock, torecess it to the focal point, a switch is closed and the laser willinitiate a pulse of radiation. In this setup, the focal point of thebeam is not in line with the end of the holder until that end isdepressed. In the extremely unlikely event of an accidental discharge ofthe laser before proper positioning of the tissue at the end of thelaser applicator, the optical arrangement will result in an energyfluence rate that is significantly low, thus causing a negligible effecton unintentional targets.

[0087] The method of this invention may be enhanced by using a laser ofa wavelength that is specifically absorbed by the skin components ofinterest (e.g., water, lipids or protein) which strongly affect thepermeation of the skin tissues. However, choosing a laser that emits astrongly absorbed wavelength is not required. Altering the lipids instratum corneum may allow enhanced permeation while avoiding the higherenergies that are necessary to affect the proteins and water.

[0088] It would be beneficial to be able to use particular lasers otherthan the Er:YAG for stratum corneum ablation or alteration. For example,laser diodes emitting radiant energy with a wavelength of 810 nm (0.8microns) are inexpensive, but such wavelength radiation is only poorlyabsorbed by tissue. In a further embodiment of this invention, a dye isadministered to the skin surface, either by application over intactstratum corneum, or by application over an Er:YAG laser treated site (sothe that deep dye penetration can occur), that absorbs such a wavelengthof radiation. For example, indocyanine green (ICG), which is a harmlessdye used in retina angiography and liver clearance studies, absorbsmaximally at 810 nm when in plasma (Stephen Flock and Steven Jacques,“Thermal Damage of Blood Vessels in a Rat Skin-Flap Window Chamber UsingIndocyanine Green and a Pulsed Alexandrite Laser: A Feasibility Study,”Laser Med. Sci. 8, 185-196, 1993). This dye, when in stratum corneum, isexpected to absorb the 810 nm radiant energy from a diode laser (e.g. aGaAlAs laser) thereby raising the temperature of the tissue, andsubsequently leading to ablation or molecular changes resulting inreduced barrier function.

[0089] Alternatively, it is possible to chemically alter the opticalproperties of the skin to enhance subsequent laser radiant energyabsorption without chemicals actually being present at the time of laserirradiation. For example, 5-aminolevulinic acid (5-ALA) is a precursorto porphyrins, which are molecules involved in hemoglobin production andbehavior. Porphyrins are strong absorbers of light. Administration of5-ALA stimulates production of porphyrins in cells, but is itselfconsumed in the process. Subsequently, there will be enhanced absorptionof radiant energy in this tissue at wavelengths where porphyrins absorb(e.g., 400 nm or 630 nm).

[0090] Another way to enhance the absorption of radiant energy instratum corneum without the addition of an exogenous absorbing compoundis to hydrate the stratum corneum by, for example, applying an occlusivebarrier to the skin prior to laser irradiation. In this situation, thewater produced within the body itself continues to diffuse through thestratum corneum and propagate out through pores in the skin, but isprevented from evaporating by the occlusive barrier. Thus, the moistureis available to further saturate the stratum corneum. As the radiantenergy emitted by the Er:YAG laser is strongly absorbed by water, thisprocess would increase the absorption coefficient of the stratumcorneum, and so less energy would be required to induce the alterationsor ablations in the stratum corneum necessary for enhanced topical drugdelivery.

[0091] Additionally, the laser ablated site eventually heals as a resultof infiltration of keratinocytes and keratin (which takes perhaps twoweeks to complete), or by the diffusion of serum up through the ablatedsites which form a clot (or eschar) which effectively seals the ablatedsite. For long term topical delivery of drugs, or for multiplesequential administrations of topical drugs, it would be beneficial tokeep the ablated site open for an extended length of time.

[0092] Thus, in an additional embodiment of this invention, the ablatedor non-ablated site is kept open by keeping the area of irradiationmoist. This is accomplished by minimizing contact of air with theablated site and/or providing fluid to keep the ablated site moistand/or biochemically similar to stratum corneum. The application of apatch (containing, for example, an ointment such as petroleum jelly oran ointment containing hydrocortisone) over the site would help to keepit open. A hydrogel patch would also serve to provide the necessarymoisture. Additionally, cytotoxic drugs such as cisplatin, bleomycin,doxurubicin, and methotrexate, for example, topically applied in lowconcentrations would locally prevent cellular infiltration and woundrepair. Furthermore, application of vitamin C (ascorbic acid), or otherknown inhibitors of melanin production, following irradiation, wouldhelp to prevent additional skin coloration in the area followingtreatment.

[0093] Pressure Wave to Enhance the Permeability of the Stratum Corneumor other Membranes

[0094] In another embodiment of the present invention, a pressuregradient is created at the ablated or altered site to force substancesthrough the skin. This technique can be used for the introduction ofcompounds (e.g., pharmaceuticals) into the body.

[0095] When laser radiant energy is absorbed by tissue, expansion (dueto heating) and/or physical movement of tissue (due to heating ornon-thermal effects such as spallation) takes place. These phenomenalead to production of propagating pressure waves, which can havefrequencies in the acoustic (20 Hz to 20,000 Hz) or ultrasonic (>20,000Hz) region of the pressure wave spectrum. For example, Flock et al.(Proc SPIE Vol. 2395, pp. 170-176, 1995) show that when a 20 ns pulsefrom a Q-switched frequency-doubled Nd:YAG laser is impacted on blood,propagating transient high pressure waves form. These pressure waves canbe spectrally decomposed to show that they consist of a spectrum offrequencies, from about 0 to greater than 4 MHz. The high pressuregradient associated with these kinds of compressional-type pressurewaves can be transformed into tension-type or stress waves which can“tear” tissue apart in a process referred to as “spallation”.

[0096] The absorption of propagating pressure waves by tissue is afunction of the tissue type and frequency of wave. Furthermore, thespeed of these pressure waves in non-bone tissue is approximately1400-1600 m/sec. Using these observations, a pressure gradient in tissuecan be created, directed either into the body or out of the body, usingpulsed laser radiant energy. To efficiently create pressure waves with apulsed laser, the pulse duration needs to be less than the time it takesfor the created heat to diffuse out of the region of interest. Theeffect is qualitatively equivalent to the effects of ultrasound ontissue. The attenuation coefficient for sound propagation in tissueincreases approximately linearly with frequency (see, for example, J.Havlice and J. Taenzer, “Medical Ultrasound Imaging: An Overview ofPrinciples and Instrumentation”, Proc. IEEE 67, 620-641, 1979), and isapproximately 1 dB/cm/MHz (note that a 20 decibel (dB) intensitydifference is equivalent to a factor of 10 in relative intensity) Thethickness of the stratum corneum is about 25 microns and the epidermisis about 200 microns. Thus, the frequency that is attenuated by 10 dBwhen propagating through the stratum corneum is 10 dB/(1dB/cm/MHz*0.0025 cm), or 4 GHz. Similarly, as strongly absorbed radiantenergy produced by a pulsed laser (say pulsed at 4 GHz) will producepropagating pressure waves of a similar frequency as the pulserepetition rate, it is possible to selectively increase the pressure inthe stratum corneum or upper layers of skin as compared to the lowerlayers, thus enhancing the diffusive properties of topically applieddrug (see, e.g., FIG. 44). A transparent, or nearly transparent, optic172, as shown in FIG. 47, can be placed on the surface of the skinto-contain the backward inertia of the propagating pressure wave orablated stratum corneum.

[0097] In an additional embodiment, as shown in FIG. 45, by modulatingthe pulse repetition frequency of the radiant energy from high to low,it is possible to create transient pressure fields that can be designedto be beneficial for enhancing the diffusive properties of a topicallyapplied pharmaceutical.

[0098] The high-frequency propagating pressure waves can also beproduced from a single laser pulse. When tissue absorbs a brief pulse oflaser irradiation, pressure waves with a spectrum of frequencies result.Some of these frequencies will propagate into lower layers in the skin,thus it may be possible to set up a reverse pressure gradient (morepressure below and less superficially) in order to enhance the diffusionof biomolecules out of the body, effectively “pumping” them through theskin.

[0099] Acoustic waves and/or spallation are believed to occur during theuse of the TRANSMEDICA™ Er:YAG laser in ablation of stratum corneum fordrug delivery or perforation, since the 2.94 micron radiant energy isabsorbed in about 1 micron of tissue, yet the tissue ablation can extendmuch deeper.

[0100] A continuous-wave laser can also be used to create pressurewaves. A continuous-wave laser beam modulated at 5-30 MHz can produce0.01-5 W/cm² pressure intensities in tissue due to expansion andcompression of sequentially heated tissue (for example, a Q-switchedEr:YAG laser (40 ns pulse) at 10 mJ and focussed to a spot size of 0.05cm, with a pulse repetition rate of 5-30 MHz, would produce in stratumcorneum a stress of about 3750 bars, or 0.025 W/cm²). It takes a fewhundred bars to cause transient permeability of cells. With this laserit requires about 0.01 W/cm² of continuous pressure wave energy toprovide effective permeation of skin.

[0101] In an additional embodiment, pressure waves are induced on thetopically applied pharmaceutical. The propagation of the wave towardsthe skin will carry some of the pharmaceutical with it (see, e.g., FIG.49).

[0102] In a further embodiment, pressure waves are induced on anabsorbing material 170 placed over the topically applied pharmaceutical(see, e.g., FIG. 48). Preferably this material is a thin film of water,however, it can be created in any liquid, solid or gas located over thetopically applied pharmaceutical. The propagation of the wave towardsthe skin will carry some of the pharmaceutical with it. Additionally,pressure waves can be induced on an absorbing material 170 (preferably athin film of water, however, it can be created in any liquid, solid orgas) placed over the target tissue (see, e.g., FIG. 46). The propagationof the wave towards the skin will increase the permeability of thestratum corneum. Subsequent to the formation of these pressure waves,the desired pharmaceutical can be applied.

[0103] In another embodiment, pressure gradients can be used to removefluids, gases or other biomolecules from the body. This can beaccomplished by focusing a beam of radiant energy down to a small volumeat some point within the tissue. The resulting heating leads to pressurewave intensities (which are proportional to the degree of heating) thatwill be greater near the focal point of the radiant energy, and lessnear the surface. The consequence of this is a pressure gradientdirected outwards thus enhancing the removal of fluids, gases or otherbiomolecules. Alternatively, propagating pressure waves created at thesurface of the skin can be focused to a point within the tissue. Thiscan be done, for example, by using a pulsed laser to irradiate a solidobject 174 above the skin, which by virtue of its shape, inducespressure waves in the tissue which converges to the focal point (see,e.g., FIG. 50). Again, the consequence of this is a pressure gradientdirected outwards thus enhancing the removal of fluids, gases or otherbiomolecules.

[0104] The pressure waves described can be created after perforation oralteration of the stratum corneum has taken place. Alternatively,pressure waves can be used as the sole means to increase the diffusiveproperties of compounds trough the skin or the removal of fluids, gasesor other biomolecules.

[0105] The pressure waves described can be created after perforation oralteration of the stratum corneum has taken place. Alternatively,pressure waves can be used as the sole means to increase the diffusiveproperties of pharmaceuticals.

[0106] Creation of Cavitation Bubbles to Increase Stratum CorneumPermeability

[0107] Cavitation bubbles, produced subsequent to the target tissuesperforation or alteration, can be used to enhance the diffusiveproperties of a topically applied drug.- While production of cavitationbubbles within the tissue is known (See, for example, R. Ensenaliev etal., “Effect of Tensile Amplitude and Temporal Characteristics onThreshold of Cavitation-Driven Ablation,” Proc. SPIE vol. 2681, pp326-333, (1996)), for the present invention, cavitation bubbles areproduced in a material on or over the surface of the skin so that theypropagate downwards (as they do because of conservation of momentum) andimpact on the stratum corneum, thereby reducing the barrier function ofthe skin. The cavitation bubbles can be created in an absorbing material170 located on or over the skin.

[0108] Cavitation has been seen to occur in water at −8 to −100 bars,(Jacques et al., Proc. SPIE vol. 1546, p. 284 (1992)). Thus, using aQ-switched Er:YAG laser (40 ns pulse) at 10 mJ and focussed to a spotsize of 0.05 cm in a thin film of water on the skin, with a pulserepetition rate of 5-30 MHz, a stress of about 3750 bars, or 0.025W/cm², is produced. This should generate the production of cavitationbubbles, which, when they contact the skin will cause mechanical and/orthermal damage thereby enhancing stratum corneum permeability.

[0109] In a preferred embodiment, the cavitation bubbles are produced ina thin film of water placed on or over the skin, however, any liquid orsolid material can be used. Subsequent to production of the cavitationbubbles a pharmaceutical is applied to the affected tissue.

[0110] In an additional embodiment, cavitation bubbles are produced inthe administered pharmaceutical subsequent to its application on theskin. Cavitation bubbles can also be produced in the stratum corneumitself before pharmaceutical application.

[0111] In a further embodiment, the target tissue is not perforated oraltered before the production of cavitation bubbles, the cavitationbubbles' impact on the stratum corneum being the only method used toincrease stratum corneum permeability.

[0112] Plasma Ablation to Increase Stratum Corneum Permeability

[0113] Plasma is a collection of ionized atoms and free electrons. Ittakes an extremely strong electric field or extremely high temperatureto ionize atoms, but at the focus of an intense pulsed laser beam(>approx. 10⁸-10¹⁰ W/cm²), such electric fields can result. Above thisenergy fluence rate, high enough temperatures can result. What one seeswhen plasma is formed is a transient bright white cloud (which resultsfrom electrons recombining with atoms resulting in light emission atmany different wavelengths which combine to appear to the eye as white).A loud cracking is usually heard when plasma is formed as a result ofsupersonic shock waves propagating out of the heated (>1000K) volumethat has high pressures (perhaps >1000 atmospheres). Since plasma is acollection of hot energetic atoms and electrons, it can be used totransfer energy to other matter, such as skin. See Walsh J T,“Optical-Thermal Response of Laser-Irradiated Tissue,” Chapter 25,pp.865-902 (Plenum Press, NY 1995), incorporated by reference herein asif fully set forth in its entirety. For example, U.S. Pat. No.5,586,981,issued to Hu, discloses the use of plasma to treat cutaneous vascular orpigmented lesions. The wavelength of the laser in Hu '981 is chosen suchthat the laser beam passes through the epidermal and dermal layers ofskin and the plasma is created within the lesion, localizing thedisruption to the targeted lesion.

[0114] A plasma can also be used to facilitate diffusion through thestratum corneum. In one embodiment of the present invention, plasma isproduced above the surface of the skin whereupon a portion of the plasmacloud will propagate outwards (and downwards) to the skin whereupon,ablation or tissue alteration will occur. Plasma can be created in aliquid, solid or gas that is placed on or over the skin, into which thelaser beam is focussed. If the plasma is created in a material with anacoustic impedance similar to tissue (say, a fluid), then the resultingpressure waves would tend to transfer most of their energy to the skin.The plasma “pressure wave” behaves similarly to a propagating pressurewave in tissue. This is due to the fact that the impedance mismatch atthe upper surface between air and solid/liquid material is high, and,furthermore, plasma, like ultrasonic energy, propagates poorly inlow-density (i.e. air) media.

[0115] In another embodiment, plasma is produced within the stratumcorneum layer. Because the energy fluence rate needed to produce theplasma is as high as approximately 10⁸ W/cm², selection of a wavelengthwith radiant energy that is strongly absorbed in tissue is not animportant concern.

[0116] Important benefits in these embodiments are that (1) the opticalabsorption of material to produce plasma is not an importantconsideration, although the energy fluence rate required to produce theplasma is less when the irradiated material strongly absorbs theincident radiant energy, and (2) there are relatively inexpensivediode-pumped Q-switched solid state lasers that can produce therequisite radiant energy (such as are available from Cutting EdgeOptronics, Inc., St, Louis, Mo.).

[0117] To obtain a peak energy fluence rate greater than orapproximately equal to the plasma creation threshold of 10⁸ W/cm², usinga pulse length of 300 μs (e.g. for the TRANSMEDICA™ Er:YAG laser, 1J for300 μs), the pulse power is 3333 W, and the spot size needs to be 0.0065mm. Alternatively, a small diode-pumped Q-switched laser can be used.Such lasers have pulse widths on the order of 10 ns, and, as such, therequisite spot size for producing plasma could be much larger.

[0118] Continuous-Wave (CW) Laser Scanning

[0119] It is possible, under machine and microprocessor control, to scana laser beam (either continuous-wave or pulsed) over the target tissue,and to minimize or eliminate thermal damage to the epidermis or adjacentanatomical structures.

[0120] For example, a scanner (made up of electro-optical or mechanicalcomponents) can be fashioned to continually move the laser beam over auser-defined area. This area can be of arbitrary size and shape. Thepath for the scan could be spiral or raster. If the laser is pulsed, ormodulated, then it would be possible to do a discrete random patternwhere the scanning optics/mechanics directs the beam to a site on theskin, the laser lases, and then the scanning optics/mechanics directsthe beam to a different site (preferable not adjacent to the first spotso that the skin has time to cool before an adjacent spot is heated up).

[0121] This scanning technique has been used before with copper-vaporlasers (in treating port-wine stains) and is in use with CO₂ lasers forthe purpose of facial resurfacing. In the case of the former, thesubepidermal blood vessels are targeted, while in the latter, about 100microns of tissue is vaporized and melted with each laser pass.

[0122] Delivery of Anesthesia

[0123] A laser can be used to perforate or alter the skin through theouter surface, such as the stratum corneum layer, but not as deep as thecapillary layer, to allow localized anesthetics to be topicallyadministered. Topically applied anesthetics must penetrate the stratumcorneum layer in order to be effective. Presently, compounds acting asdrug carriers are used to facilitate the transdermal diffusion of somedrugs. These carriers sometimes change the behavior of the drug, or arethemselves toxic.

[0124] With the other parameters set, the magnitude of the laser pumpsource will determine the intensity of the laser pulse, which will inturn determine the depth of the resultant perforation or alteration.Therefore, various settings on the laser can be adjusted to allowperforation or alteration of different thicknesses of stratum corneum.

[0125] Optionally, a beam-dump can be positioned in such a way as not toimpede the use of the laser for perforation or alteration ofextremities. The beam-dump will absorb any stray electromagneticradiation from the beam that is not absorbed by the tissue, thuspreventing any scattered rays from causing damage. The beam-dump can bedesigned so as to be easily removed for situations when the presence ofthe beam-dump would impede the placement of a body part on theapplicator.

[0126] This method of delivering anesthetic creates a very small zone inwhich tissue is irradiated, and only an extremely small zone of thermalnecrosis. A practical round irradiation site can range from 0.1-5.0 cmin diameter, while a slit shaped hole can range from approximately0.05-0.5 mm in width and up to approximately 2.5 mm in length, althoughother slit sizes and lengths can be used. As a result, healing isquicker or as quick as the healing after a skin puncture with a sharpimplement. After irradiation, anesthetic can then be applied directly tothe skin or in a pharmaceutically acceptable formulation such as acream, ointment, lotion or patch.

[0127] Alternatively, the delivery zone can be enlarged by strategiclocation of the irradiation sites and by the use of multiple sites. Forexample, a region of the skin may be anesthetized by first scanning thedesired area with a pulsing laser such that each pulse is sufficient tocause perforation or alteration. This can be accomplished with modulateddiode or related microchip lasers, which deliver single pulses withtemporal widths in the 1 femtosecond to 1 ms range. (See D. Stern etal., “Corneal Ablation by Nanosecond, Picosecond, and Femtosecond Lasersat 532 and 625 nm,” Corneal Laser Ablation, vol. 107, pp. 587-592(1989), incorporated herein by reference, which discloses the use ofpulse lengths down to 1 femtosecond). Anesthetic (e.g., 10% lidocaine)would then be applied over the treated area to achieve a zone ofanesthesia.

[0128] The present method can be used for transport of a variety ofanesthetics. These anesthetics are different in their system and localtoxicity, degree of anesthesia produced, time to onset of anesthesia,length of time that anesthesia prevails, biodistribution, and sideeffects. Examples of local anesthetic in facial skin-resurfacing with alaser can be found in Fitzpatrick R. E., Williams B. Goldman M. P.,“Preoperative Anesthesia and Postoperative Considerations in LaserResurfacing,” Semin. Cutan. Med. Surg. 15(3):170-6, 1996. A partial listconsists of: cocaine, procaine, mepivacaine, etidocaine, ropivacaine,bupivacaine, lidocaine, tetracain, dibucaine, prilocaine,chloroprocaine, hexlcaine, fentanly, procainamide, piperocaine, MEGX(des-ethyl lidocaine) and PPX (pipecolyl xylidine). A reference on localanesthetic issues can be found in Rudolph de Jong, “Local Anesthetics,”Mosby-Year Book: St Louis, 1994.

[0129] Delivery of Pharmaceuticals

[0130] The present method can also be used to deliver pharmaceuticals ina manner similar to the above described delivery of anesthesia. Byappropriate modification of the power level, and/or the spot size of thelaser beam, perforations or alterations can be made which do notpenetrate as deep as the capillary layer. These perforations oralterations can be made through only the outer surfaces, such as thestratum corneum layer or both the stratum corneum layer and theepidermis. Optionally an optical beam-splitter or multiply pulsed lasercan be employed so that either single or multiple perforations oralterations within a desired area can be made. After perforation oralteration, the pharmaceutical can be applied directly to the skin or ina pharmaceutically acceptable formulation such as a cream, ointment,lotion or patch.

[0131] The present method can be used for transport of a variety ofsystemically acting pharmaceutical substances. For example nitroglycerinand antinauseants such as scopolamine; antibiotics such as tetracycline,streptomycin, sulfa drugs, kanamycin, neomycin, penicillin, andchloramphenicol; various hormones, such as parathyroid hormone, growthhormonie, gonadotropins, insulin, ACTH, somatostatin, prolactin,placental lactogen, melanocyte stimulating hormone, thyrotropin,parathyroid hormone, calcitonin, enkephalin, and angiotensin; steroid ornon-steroid anti-inflammatory agents, and systemic antibiotic, antiviralor antifungal agents.

[0132] Delivery of Locally Acting Pharmaceuticals

[0133] Laser-assisted perforation or alteration provides a unique sitefor local uptake of pharmaceutical substances to a desired region. Thus,high local concentrations of a substance may be achieved which areeffective in a region proximal to the irradiated site by virtue oflimited dilution near the site of application. This embodiment of thepresent invention provides a means for treating local pain orinfections, or for application of a substance to a small specified area,directly, thus eliminating the need to provide high, potentially toxicamounts systemically through oral or i.v. administration. Locally actingpharmaceuticals such as alprostadil (for example Caverject fromPharmacia & Upjohn), various antibiotics, antiviral or antifungalagents, or chemotherapy or anti-cancer agents, can be delivered usingthis method to treat regions proximal to the delivery site. Protein orDNA based biopharmaceutical agents can also be delivered using thismethod.

[0134] Immunization

[0135] As for delivery of pharmaceuticals, antigens derived from avirus, bacteria or other agent which stimulates an immune response canbe administered through the skin for immunization purposes. Theperforations or alterations are made through the outer layers of theskin, either singly or multiply, and the immunogen is provided in anappropriate formulation. For booster immunizations, where delivery overa period of time increases the immune response, the immunogen can beprovided in a formulation which penetrates slowly through theperforations or alterations, but at a rate faster than possible throughunperforated or unaltered skin.

[0136] This approach offers clinicians a new approach for immunizationsby solving some of the problems encountered with other routes ofadministration (e.g. many vaccine preparations are not efficaciousthrough oral or intravenous routes). Further, the skin is often thefirst line of defense for invading-microbes and the immune response inthe skin is partially composed of Immunoglobulin A (IgA) antibodies likethat of the mucous membranes. Scientists have long sought ways to inducemucosal immunity using various vaccine preparations. Unfortunately theyhave been met with limited success because in order to generate an IgAresponse, vaccine preparations must be delivered to mucous membranes inthe gut or sinuses which are difficult to reach with standardformulations. By immunizing intradermally, unique populations ofantibodies may be generated which include IgA, a critical element ofmucosal immunity. This laser-assisted intradermal method of antigenpresentation thereby may be used as a means to generate IgA antibodiesagainst invading organisms.

[0137] Delivery of Allergens

[0138] Traditional allergy testing requires the allergist to makemultiple pricks on the patient's skin and apply specific allergens tomake a determination regarding intradermal hypersensitivity. The methodof this invention can be used to deliver allergens reproducibly forallergy testing. Multiple perforations or alterations can be madethrough the outer layer of the skin without penetrating to the capillarylevel. A variety of allergens can then be applied to the skin, as in askin patch test. One of the benefits of this methodology is that thestratum corneum barrier function compromise (i.e. laser irradiation) ismore consistent than pricks made with a sharp.

[0139] Delivery of Permeation Enhancers

[0140] Certain compounds may be used to enhance the permeation ofsubstances into the tissues below perforated or ablated stratum corneum.Such enhancers include DMSO, alcohols and salts. Other compoundsspecifically aid permeation based on specific effects such as byincreasing ablation or improving capillary flow by limiting inflammation(i.e. salicylic acid). The method of this invention can be used todeliver these permeation enhancers. Multiple or single perforations oralterations can be made through the outer layer of the skin withoutpenetrating to the capillary level. Subsequently, a variety ofpermeation enhancers can be applied to the irradiated site, as in a skinpatch.

[0141] Delivery of Anti-Inflammatory Drugs

[0142] Analgesics and other non-steroid anti-inflammatory agents, aswell as steroid anti-inflammatory agents may be caused to permeatethrough perforated or altered stratum corneum to locally affect tissuewithin proximity of the irradiated site. For example, anti-inflammatoryagents such as Indocin (Merck & Co.), a non-steroidal drug, areeffective agents for treatment of rheumatoid arthritis when takenorally, yet sometimes debilitating gastrointestinal effects can occur.By administering such agents through laser-assisted perforation oralteration sites, these potentially dangerous gastrointestinalcomplications may be avoided. Further, high local concentrations of theagents may be achieved more readily near the site of irradiation asopposed to the systemic concentrations achieved when orallyadministered.

[0143] Drawing Fluids, Gases or Other Biomolecules

[0144] A laser can be used to perforate or alter the skin through theouter surface, such as the stratum corneum layer, but not as deep as thecapillary layer, to allow the collection of fluids, gases or otherbiomolecules. The fluid, gas or other biomolecule can be used for a widevariety of tests. With the other parameters set, the magnitude of thelaser pump source will determine the intensity of the laser pulse, whichwill in turn determine the depth of the resultant perforation oralteration. Therefore, various settings on the laser can be adjusted toallow penetration of different thicknesses of skin.

[0145] Optionally, a beam-dump can be positioned in such a way as not toimpede the use of the laser for perforation or alteration ofextremities. The beam-dump will absorb any stray electromagneticradiation from the beam that is not absorbed by the tissue, thuspreventing any scattered rays from causing damage. The beam-dump can bedesigned to be easily removed for situations when the presence of thebeam-dump Would impede the placement of a body part on the applicator.

[0146] This method of drawing fluids, gases or other biomolecule createsa very small zone in which tissue is irradiated, and only an extremelysmall zone of thermal necrosis. For example, a practical round hole canrange from about 0.1-1 mm in diameter, while a slit shaped hole canrange from about approximately 0.05-0.5 mm in width and up toapproximately 2.5 mm in length. As a result, healing is quicker or asquick as the healing after a skin puncture with a sharp implement.

[0147] The fluid, gas or other biomolecule can be collected into asuitable vessel, such as a small test tube or a capillary tube, or in acontainer unit placed between the laser and the tissue as describedabove. The process does not require contact. Therefore, neither thepatient, the fluid, gas or other biomolecule to be drawn, or theinstrument creating the perforation or alteration is contaminated.

[0148] The technique of the present invention may be used to sampleextracellular fluid in order to quantify glucose or the like. Glucose ispresent in the extracellular fluid in the same concentration as (or in aknown proportion to) the glucose level in blood (e.g. Lonnroth P.Strindberg L. Validation of the “internal reference technique” forcalibrating micro dialysis catheters in situ, Acta PhysiologicalScandinavica, 153(4):37580, 1995 Apr.).

[0149] The perforation or alteration of the stratum corneum causes alocal increase, in the water loss through the skin (referred to astransepidermal water loss, or TEWL). As shown in FIG. 27, withincreasing laser energy fluence (J/cm²), there is a correspondingincrease in water loss. The tape strip data is a positive control thatproves that the measurement is indeed sensitive to increased skin waterevaporation.

[0150] Two of the energies used in FIG. 27, 40 mJ and 80 mJ (1.27 and2.55 J/cm²) are non-ablative and therefore show that non-ablativeenergies allow the alteration of the barrier function of stratumcorneum, thereby resulting in enhanced transepidermal water loss whichcan provide a diagnostic sample of extracellular fluid.

[0151] Besides glucose, other compounds and pathological agents also canbe assayed in extracellular fluid. For example, HIV is presentextracellularly and may be assayed according to the present method. Thebenefit to obtaining samples for HIV analysis without having to drawblood with a sharp that can subsequently contaminate the health-careprovider is obvious. Additionally, the present invention can be used toemploy lasers non-ablatively to reduce or eliminate the barrierproperties of non-skin barriers in the human body, such as theblood-brain interface membranes, such as that positioned between thebrains third ventricle and the hypothalamus, the sclera of the eye orany mucosal tissue, such as in the oral cavity.

[0152] Alteration Without Ablation

[0153] There are advantages to the technique of altering and notablating the stratum corneum. In a preferred embodiment, the skin isaltered, not ablated, so that its structural and biochemical makeupallow drugs to permeate. The consequence of this embodiment is: (1) theskin after irradiation still presents a barrier, albeit reduced, toexternal factors such as viruses and chemical toxins; (2) less energy isrequired than is required to ablate the stratum corneum, thus smallerand cheaper lasers can be used; and (3) less tissue damage occurs, thusresulting in more rapid and efficient healing.

[0154] Radiant Energy vs Laser Radiant Energy

[0155] The radiant energy emitted by lasers has the properties of beingcoherent, monochromatic, collimated and (typically) intense.Nevertheless, to enhance transdermal drug delivery or fluid, gas orbiomolecule collection, the radiant energy used need not have theseproperties, or alternatively, can have one of all of these properties,but can be produced by a non-laser source

[0156] For example, the pulsed light output of a pulsed xenon flashlampcan be filtered with an optical filter or other wavelength selectiondevice, and a particular range of wavelengths can be selected out of theradiant energy output. While the incoherent and quasi-monochromaticoutput of such a configuration cannot be focussed down to a small spotas can coherent radiant energy, for the aforementioned purpose that maynot be important as it could be focused down to a spot with a diameteron the order of millimeters. Such light sources can be used in acontinuous wave mode if desirable.

[0157] The infrared output of incandescent lights is significantly morethan their output in the visible, and so such light sources, if suitablyfiltered to eliminate undesirable energy that does not reduce barrierfunction, could be used for this purpose. In another embodiment of theinvention, it would be possible to use an intense incandescent light(such as a halogen lamp), filter it with an optical filter or similardevice, and used the continuous-wave radiant energy output to decreasethe barrier function of stratum corneum without causing ablation. All ofthese sources of radiant energy can be used to produce pulses, orcontinuos-wave radiant energy.

[0158] Laser Device

[0159] The practice of the present invention has been found to beeffectively performed by various types of lasers; for example, theTRANSMEDICA™ Er:YAG laser perforator, or the Schwartz Electro-OpticalEr:YAG laser. Preferably, any pulsed laser producing energy that isstrongly absorbed in tissue may be used in the practice of the presentinvention to produce the same result at a nonablative wavelength, pulselength, pulse energy, pulse number, and pulse rate. However, laserswhich produce energy that is not strongly absorbed by tissue may also beused, albeit less effectively, in the practice of this invention.Additionally, as described herein, continuous-wave lasers may also beused in the practice of this invention.

[0160]FIGS. 1 and 2 are diagrammatic representations a typical laserthat can be used for this invention. As shown in FIGS. 1 and 2, atypical laser comprises a power connection which can be either astandard electrical supply 10, or optionally a rechargeable battery pack12, optionally with a power interlock switch 14 for safety purposes; ahigh voltage pulse-forming network 16; a laser pump-cavity 18 containinga laser rod 20, preferably Er:YAG; a means for exciting the laser rod,preferably a flashlamp 22 supported within the laser pump-cavity; anoptical resonator comprised of a high reflectance mirror 24 positionedposterior to the laser rod and an output coupling mirror 26 positionedanterior to the laser rod; a transmitting focusing lens 28 positionedbeyond the output coupling mirror; optionally a second focusingcylindrical lens 27 positioned between the output coupling mirror andthe transmitting focusing lens; an applicator 30 for positioning thesubject skin at the focal point of the laser beam, which is optionallyheated for example with a thermoelectric heater 32, attached to thelaser housing 34; an interlock 36 positioned between the applicator andthe power supply; and optionally a beam dump 38 attached to theapplicator with a fingertip access port 40.

[0161] The laser typically draws power from a standard 110 V or 220 V ACpower supply 10 (single phase, 50 or 60 Hz) which is rectified and usedto charge up a bank of capacitors included in the high voltagepulse-forming network 16. Optionally, a rechargeable battery pack 12 canbe used instead. The bank of capacitors establishes a high DC voltageacross a high output flashlamp 22. Optionally a power interlock 14, suchas a keyswitch, can be provided which will prevent accidental chargingof the capacitors and thus accidental laser excitation. A furtherinterlock can be added to the laser at the applicator, such as aspring-loaded interlock 36, so that discharge of the capacitors requiresboth interlocks to be enabled.

[0162] With the depression of a switch, a voltage pulse can besuperimposed on the already existing voltage across the flashlamp inorder to cause the flashlamp to conduct, and, as a consequence, initiatethe flash. The light energy from the flashlamp is located in the lasercavity 18 that has a shape such that most of the light energy isefficiently directed to the laser rod 20, which absorbs the lightenergy, and, upon de-excitation, subsequently lases. The laser cavitymirrors of low 26 and high 24 reflectivity, positioned collinearly withthe long-axis of the laser rod, serve to amplify and align the laserbeam.

[0163] Optionally, as shown in FIG. 12 the laser cavity mirrors comprisecoatings 124, 126, applied to ends of the crystal element and which havethe desired reflectivity characteristics. In a preferred embodiment anEr:YAG crystal is grown in a boule two inches in diameter and fiveinches long. The boule is core drilled to produce a rod 5-6 millimetersin diameter and five inches long. The ends of the crystal are ground andpolished. The output end, that is the end of the element from which thelaser beam exits, is perpendicular to the center axis of the rod within5 arc minutes. The flatness of the output end is {fraction (1/10)} awavelength (2.9 microns) over 90% of the aperture. The high reflectanceend, that is the end opposite the output end, comprises a two meterconvex spherical radius. The polished ends are polished so that thereare an average of ten scratches and five digs per Military SpecificationMil-0-13830A. Scratch and dig are subjective measurements that measurethe visibility of large surface defects such as defined by U.S. militarystandards. Ratings consist of two numbers, the first being thevisibility of scratches and the latter being the count of digs (smallpits). A #10 scratch appears identical to a 10 micron wide standardscratch while a #1 dig appears identical to a 0.01 mm diameter standardpit. For collimated laser beams, one normally would use optics withbetter than a 40-20 scratch-dig rating.

[0164] Many coatings are available from Rocky Mountain Instruments,Colorado Springs, Colo. The coating is then vacuum deposited on theends. For a 2.9 micron wavelength the coatings for the rear mirroredsurface 124 should have a reflectivity of greater than 99%. The coatingfor the output end surface, by contrast, should have a reflectance ofbetween 93% and 95%, but other mirrored surfaces with reflectivity aslow as 80% are useful. Other vacuum deposited metallic coatings withknown reflectance characteristics are widely available for use withother laser wavelengths.

[0165] The general equation which defines the reflectivity of themirrors in a laser cavity necessary for the threshold for populationinversion is:

R₁R₂(1−a_(L))² exp[(g₂₁−α)2L]1

[0166] where the R₁ and R₂ are the mirrors' reflectivities, a_(L) is thetotal scattering losses per pass through the cavity, g₂₁ is the gaincoefficient which is the ratio of the stimulated emission cross sectionand population inversion density, α is the absorption of the radiationover one length of the laser cavity, and L is the length of the lasercavity. Using the above equation, one can select a coating with theappropriate spectral reflectivity from the following references. W.Driscoll and W. Vaughan, “Handbook of Optics,” ch. 8, eds., McGraw-Hill:NY (1978); M. Bass, et al., “Handbook of Optics,” ch. 35, eds., McGrawHill: NY (1995).

[0167] Optionally, as also shown in FIG. 12, the crystal element may benon-rigidly mounted. In FIG. 12 an elastomeric material O-ring 128 is ina slot in the laser head assembly housing 120 located at the highreflectance end of the crystal element. A second elastomeric materialO-ring 130 is in a second slot in the laser head assembly at the outputend of the crystal element. The O-rings contact the crystal element byconcentrically receiving the element as shown. However, elastomericmaterial of any shape may be used so long as it provides elastomericsupport for the element (directly or indirectly) and thereby permitsthermal expansion of the element. Optionally, the flash lamp 22 may alsobe non-rigidly mounted. FIG. 12 shows elastomeric O-rings 134, 136, eachin its own slot within the laser head assembly housing. In FIG. 12 theO-rings 134 and 136 concentrically receive the flash lamp. However, theflash lamp may be supported by elastomeric material of other shapes,including shapes without openings.

[0168] Optionally, as shown in FIG. 3, a diode laser 42 that produces apump-beam collinear with the long-axis of the laser crystal can be usedinstead of the flashlamp to excite the crystal. The pump-beam of thislaser is collimated with a collimating lens 44, and transmitted to theprimary laser rod through the high reflectance infrared mirror 45. Thishigh reflectance mirror allows the diode pump laser beam to betransmitted, while reflecting infrared light from the primary laser.

[0169] The Er:YAG lasing material is the preferred material for thelaser rod because the wavelength of the electromagnetic energy emittedby this laser, 2.94 microns, is very near one of the peak absorptionwavelengths (approximately 3 microns) of water. Thus, this wavelength isstrongly absorbed by water and tissue. The rapid heating of water andtissue causes perforation or alteration of the skin.

[0170] Other useful lasing material is any material which, when inducedto lase, emits a wavelength that is strongly absorbed by tissue, such asthrough absorption by water, nucleic acids, proteins or lipids, andconsequently causes the required perforation or alteration of the skin(although strong absorption is not required). A laser can effectivelycut or alter tissue to create the desired perforations or alterationswhere tissue exhibits an absorption coefficient of 10-10,000 cm⁻¹.Examples of useful lasing elements are pulsed CO₂ lasers, Ho:YAG(holmium:YAG), Er:YAP, Er/Cr:YSGG (erbium/chromium: yttrium, scandium,gallium, garnet; 2.796 microns), Ho:YSGG (holmium: YSGG; 2.088 microns),Er:GGSG (erbium: gadolinium, gallium, scandium, garnet), Er:YLF (erbium:yttrium, lithium, fluoride; 2.8 microns), Tm:YAG (thulium: YAG; 2.01microns), Ho:YAG (holmium: YAG; 2.127 microns); Ho/Nd:YAlO₃(holmium/neodymium: yttrium, alurninate; 2.85-2.92 microns), cobalt:MgF₂(cobalt: magnesium fluoride; 1.75-2.5 microns), HF chemical (hydrogenfluoride; 2.6-3 microns), DF chemical (deuterium fluoride; 3.64microns), carbon monoxide (5-6 microns), deep UV lasers, and frequencytripled Nd:YAG (neodymium:YAG, where the laser beam is passed throughcrystals which cause the frequency to be tripled).

[0171] Utilizing current technology, some of these laser materialsprovide the added benefit of small size, allowing the laser to be smalland portable. For example, in addition to Er:YAG, Ho:YAG lasers alsoprovide this advantage.

[0172] Solid state lasers, including but not limited to those listedabove, may employ a polished barrel crystal rod. The rod surface mayalso contain a matte finish as shown in FIG. 13. However, both of theseconfigurations can result in halo rays that surround the central outputbeam. Furthermore, an all-matte finish, although capable of diminishinghalo rays relative to a polished rod, will cause a relatively largedecrease in the overall laser energy output. In order to reduce halorays and otherwise affect beam mode, the matte finish can be present onbands of various lengths along the rod, each band extending around theentire circumference of the rod. Alternatively, the matte finish may bepresent in bands along only part of the rod's circumference. FIG. 14shows a laser crystal element in which the matte finish is present uponthe full circumference of the element along two-thirds of its length.Alternatively, as shown in FIG. 15, matte stripes may be presentlongitudinally along the full length of the rod. The longitudinalstripes may alternatively exist along only part of the length of therod, such as in stripes of various lengths. A combination of theforegoing techniques may be used to affect beam shape. Other variationsof patterns may also be employed in light of the beam shape desired. Thespecific pattern may be-determined based on the starting configurationof the beam from a 100% polished element in light of the desired finalbeam shape and energy level. A complete matte finish element may also beused as the starting reference point.

[0173] For purposes of beam shape control, any surface finish of greaterthan 30 microinches is considered matte. A microinch equals onemillionth (0.000001) inch, which is a common unit of measurementemployed in establishing standard roughness unit values. The degree ofroughness is calculated using the root-mean-square average of thedistances in microinches above or below the mean reference line, bytaking the square root of the mean of the sum of the squares of thesedistances. Although matte surfaces of greater than 500 microinches maybe used to affect beam shape, such a finish will seriously reduce theamount of light energy that enters the crystal rod, thereby reducing thelaser's energy.

[0174] To remove the beam halo, a matte area of approximately 50microinches is present around the full circumference of an Er:YAG laserrod for two-thirds the length of the rod. The non-matte areas of the rodare less than 10 microinches. A baseline test of the non-matte rod canbe first conducted to determine the baseline beam shape and energy ofthe rod. The matte areas are then obtained by roughing the polishedcrystal laser rod, such as with a diamond hone or grit blaster. Thespecific pattern of matte can be determined with respect to the desiredbeam shape and required beam energy level. This results in a greatlyreduced beam halo. The rod may also be developed by core drilling aboule of crystal so that it leaves an overall matte finish and thenpolishing the desired areas, or by refining a partially matte, partiallypolished boule to achieve the desired pattern.

[0175] The beam shape of a crystal laser rod element may alternativelybe modified as in FIG. 16 by surrounding the rod 20 in a material 160which is transparent to the exciting light but has an index ofrefraction greater than the rod. Such a modification can reduce the haloof the beam by increasing the escape probability of off-axis photonswithin the crystal. This procedure may be used in place of or inaddition to the foregoing matte procedure.

[0176] The emitted laser beam is focused down to a millimeter orsubmillimeter sized spot with the use of the focusing lens 28.Consideration of laser safety issues suggests that a short focal lengthfocusing lens be used to ensure that the energy fluence rate (W/cm²) islow except at the focus of the lens where the tissue sample to beperforated or altered is positioned. Consequently, the hazard of thelaser beam is minimized.

[0177] The beam can be focused so that it is narrower along one axisthan the other in order to produce a slit-shaped perforation oralteration through the use of a cylindrical focusing lens 27. This lens,which focuses the beam along one axis, is placed in series with thetransmitting focusing lens 28. When perforations or alterations areslit-shaped, the patient discomfort or pain associated with theperforation or alteration is considerably reduced.

[0178] Optionally, the beam can be broadened, for instance through theuse of a concave diverging lens 46 (FIG. 4) prior to focusing throughthe focusing lens 28. This broadening of the beam results in a laserbeam with an even lower energy fluence rate a short distance beyond thefocal point, consequently reducing the hazard level. Furthermore, thisoptical arrangement reduces the optical aberrations in the laser spot atthe treatment position, consequently resulting in a more preciseperforation or alteration.

[0179] Also optionally, the beam can be split by means of abeam-splitter to create multiple beams capable of perforating oraltering several sites simultaneously or near simultaneously. FIG. 5provides two variations of useful beam splitters. In one version,multiple beam splitters 48 such as partially silvered mirrors, dichroicmirrors, or beam-splitting prisms can be provided after the beam isfocused. Alternatively, an acousto-optic modulator 52 can be suppliedwith modulated high voltage to drive the modulator 52 and bend the beam.This modulator is outside the laser cavity. It functions by deflectingthe laser beam sequentially and rapidly at a variety of angles tosimulate the production of multiple beams.

[0180] Portability

[0181] Currently, using a portable TRANSMEDICA™ Er:YAG laser, the unitdischarges once per 20-30 seconds. This can be increased by adding abattery and capacitor and cooling system to obtain a quicker cycle.Multiple capacitors can be strung together to get the discharge ratedown to once every 5 or 10 seconds (sequentially charging the capacitorbanks). Thus, getting a higher repetition rate than with a singlecapacitor.

[0182] The TRANSMEDICA™ Er:YAG laser incorporates a flashlamp, theoutput of which is initiated by a high-voltage pulse of electricityproduced by a charged capacitor bank. Due to the high voltages requiredto excite the flashlamp, and because the referred to version of thelaser incorporates dry cells to run (thus the charging current is muchless than a wall-plug could provide), then the capacitors take about 20seconds to sufficiently charge. Thus, if a pulse repetition rate of 1pulse/20 seconds is desirable, it would be suitable to have multiplecapacitor banks that charge sequentially (i.e. as one bank fires theflashlamp, another bank, which has been recharging, fires, and so on).Thus, the pulse repetition rate is limited only be the number ofcapacitor banks incorporated into the device (and is also limited by theefficiency of waste-heat removal from the laser cavity).

[0183] A small heater, such as a thermoelectric heater 32, is optionallypositioned at the end of the laser applicator proximal to the site ofperforation. The heater raises the temperature of the tissue to beperforated or altered prior to laser irradiation. This increases thevolume of fluid collected when the device is used for that purpose. Asuggested range for skin temperature is between 36° C, and 45° C.,although any temperature which causes vasodilation and the resultingincrease in blood flow without altering the blood chemistry isappropriate.

[0184] Container Unit

[0185] A container unit 68 is optionally fitted into the laser housingand is positioned proximal to the perforation or alteration site. Thecontainer unit reduces the intensity of the sound produced when thelaser beam perforates or alters the patient's tissue, increases theefficiency of fluid, gas or other biomolecule collection, and collectsthe ablated tissue and other matter released by the perforation. Thecontainer unit can be shaped so as to allow easy insertion into thelaser housing and to provide a friction fit within the laser housing.FIG. 8 shows a typical container unit inserted into the laser housingand placed over the perforation site.

[0186] The container unit 68 comprises a main receptacle 82, including alens 84. The main receptacle collects the fluid, gas or otherbiomolecule sample, the ablated tissue, and/or other matter released bythe perforation. The lens is placed such that the laser beam may passthrough the lens to the perforation site but so that the matter releasedby the perforation does not splatter back onto the applicator. Thecontainer unit also optionally includes a base 86, attached to thereceptacle. The base can optionally be formed so as to be capable ofbeing inserted into the applicator to disengage a safety mechanism ofthe laser, thereby allowing the laser beam to be emitted.

[0187] As shown in FIG. 17, the shape and size of the container unit 68are such as to allow placement next to or insertion into the applicator,and to allow collection of the fluid, gas or other biomolecule samples,ablated tissue, and/or other matter released by the perforation oralteration. Examples of shapes that the main receptacle may take includecylinders, bullet shapes, cones, polygons and free form shapes.Preferably, the container unit has a main receptacle, with a volume ofaround 1-2 milliliters. However, larger and smaller receptacles willalso function appropriately.

[0188] The lens 84, which allows the laser beam to pass through whilepreventing biological and other matter from splattering back onto theapplicator, is at least partially transparent. The lens is constructedof a material that transmits the laser wavelength utilized and ispositioned in the pathway of the laser beam, at the end of the containerunit proximal to the beam. The transmitting material can be quartz, butother examples of suitable infrared transmitting materials include rocksalt, germanium, glass, crystalline sapphire, polyvinyl chloride andpolyethylene. However, these materials should not contain impuritiesthat absorb the laser beam energy. As shown in FIG. 20, the lens mayoptionally include a mask of non-transmitting material 85 such that thelens may shape the portion of the beam that is transmitted to theperforation site.

[0189] The main receptacle 82 is formed by the lens and a wall 88,preferably extending essentially away from the perimeter of the lens.The open end of the main receptacle or rim 90 is placed adjacent to theperforation or alteration site. The area defined by the lens, wall ofthe main receptacle and perforation or alteration site is therebysubstantially enclosed during the operation of the laser.

[0190] The base 86 is the part of the container unit that can optionallybe inserted into the applicator. The base may comprise a cylinder, aplurality of prongs or other structure. The base may optionally havethreading. Optionally, the base, when fully inserted, disengages asafety mechanism of the laser, allowing the emission of the laser beam.

[0191] A typical container unit can comprise a cylindrical mainreceptacle 82, a cylindrical base 86, and an at least partiallytransparent circular lens 84 in the area between the main receptacle andbase. Optionally, the lens may include a mask that shapes the beam thatperforates the tissue. The interior of the main receptacle is optionallycoated with anticoagulating and/or preservative chemicals. The containerunit can be constructed of glass or plastic. The container unit isoptionally disposable.

[0192]FIG. 19 shows examples of the use of a container unit with a laserfor the purpose of drawing fluids, gases or other biomolecules or toadminister pharmaceuticals. In this embodiment the applicator 30 issurrounded by the housing 34. The container unit is inserted in theapplicator 30 and aligned so as to be capable of defeating the interlock36. The base 86 of the container unit in this embodiment is within theapplicator 30, while the rim 90 of the receptacle 82 is located adjacentto the tissue to be perforated.

[0193] Additionally, the container unit can be evacuated. The optionalvacuum in the container unit exerts a less than interstitial fluid orthe pressure of gases in the blood over the perforation or alterationsite, thereby increasing the efficiency in fluid, gas or otherbiomolecule collection. The container unit is optionally coated withanticoagulating and/or preservative chemicals. The container unit's endproximal to the perforation or alteration site is optionally sealedair-tight with a plug 70. The plug is constructed of material ofsuitable flexibility to conform to the contours of the perforation site(e.g., the finger). The desired perforation or alteration site is firmlypressed against the plug. The plug's material is preferably impermeableto gas transfer. Furthermore, the plug's material is thin enough topermit perforation of the material as well as perforation of the skin bythe laser. The plug can be constructed of rubber, for example.

[0194] The plug perforation center 74, as shown in FIG. 9, is preferablyconstructed of a thin rubber material. The thickness of the plug is suchthat the plug can maintain the vacuum prior to perforation, and thelaser can perforate both the plug and the tissue adjacent to the plug.For use with an Er:YAG laser, the plug can be in the range ofapproximately about 100 to 500 microns thick.

[0195] The plug perforation center 74 is large enough to cover theperforation or alteration site. Optionally, the perforated site is around hole with an approximate diameter ranging from about 0.1-1 mm, orslit shaped with an approximate width of about 0.05-0.5 mm and anapproximate length up to about 2.5 mm. Thus, the plug perforation centeris sufficiently large to cover perforation sites of these sizes.

[0196] As shown in FIG. 10, the container unit 68 can include a hole 76through which the laser passes. In this example, the container unitoptionally solely collects ablated tissue. As in the other examples, thesite of irradiation is firmly pressed against the container unit. Thecontainer unit can optionally include a plug proximal to the perforationsite, however it is not essential because there is no need to maintain avacuum. The container unit reduces the noise created from interactionbetween the laser beam and the patient's tissue and thus alleviates thepatient's anxiety and stress.

[0197] The container may also be modified to hold, or receive through anopening, a pharmaceutical or other substance, which may then bedelivered simultaneously, or shortly after irradiation occurs. FIG. 11shows an example of a container with a built-in drug reservoir androll-on apparatus for delivery. FIG. 18 shows a container with anapplicator which in turn comprises an atomizer with attached highpressure gas cylinder.

[0198] Optionally, the container unit is disposable, so that thecontainer unit and plug can be discarded after use.

[0199] In order to sterilize the skin before perforation or alteration,a sterile alcohol-impregnated patch of paper or other thin material canoptionally be placed over the site to be perforated. This material canalso prevent the blowing off of potentially infected tissue in the plumereleased by the perforation. The material must have low bulk absorptioncharacteristics for the wavelength of the laser beam. Examples of suchmaterial include, but are not limited to, a thin layer of glass, quartz,mica, or sapphire. Alternatively, a thin layer of plastic, such as afilm of polyvinyl chloride or polyethylene, can be placed over the skin.Although the laser beam may perforate the plastic, the plastic preventsmost of the plume from flying out and thus decreases any potential riskof contamination from infected tissue. Additionally, a layer of aviscous sterile substance such as vaseline can be added to thetransparent material or plastic film to increase adherence of thematerial or plastic to the skin and further decrease plumecontamination. Additionally, such a patch can be used to deliverallergens, local anesthetics or other pharmaceuticals as describedbelow.

[0200] Examples of such a patch are provided in FIGS. 6 and 7. In FIG.6, alcohol impregnated paper 54 is surrounded by a temporary adhesivestrip 58. Side views of two alternative patches are shown in FIG. 7,where a sterilizing alcohol, antibiotic ointment, allergen, orpharmaceutical is present in the central region of the patch 60. Thismaterial is held in place by a paper or plastic layer 62, optionallywith a laser-transparent material 64. Examples of such material include,but are not limited to, mica, quartz or sapphire which is transparent tothe laser beam at the center of the patch. However, the material neednot be totally transparent. The patch can be placed on the skin using anadhesive 66.

[0201] Modulated Laser

[0202] In addition to the pulsed lasers listed above, a modulated lasercan be used to duplicate a pulsed laser for the purpose of enhancingtopical drug delivery, as well as enhancing the removal of fluids, gasesor other biomolecules. This is accomplished by chopping the output ofthe continuous-wave laser by either modulating the laser outputmechanically, optically or by other means such as a saturable absorber.(See, e.g., Jeff Hecht, “The Laser Guidebook,” McGraw-Hill:NY, 1992).Examples of continuous-wave lasers include CO₂ which lases over a rangebetween 9-11 microns (e.g. Edinburgh Instruments, Edinburgh, UK),Nd:YAG, Thullium:YAG (Tm:YAG), which lases at 2.1 microns (e.g. CLRPhotonics Inc., Boulder Colo.), semiconductor (diode) lasers which laseover a range from 1.0-2.0 microns (SDL Inc., San Jose, Calif.).

[0203] The chopping of the laser output (for example, with a mechanicalchopper from Stanford Research Instruments Inc., Sunnyvale Calif.) willpreferably result in discrete moments of irradiation with temporalwidths from a few tenths of milliseconds, down to nanoseconds orpicoseconds. Alternatively, in the case of diode lasers, the lasingprocess can be modulated by modulating the laser excitation current. Amodulator for a laser diode power supply can be purchased from SDL Inc.,San Jose, Calif. Alternatively, the continuous-wave beam can beoptically modulated using, for example, an electro-optic cell (e.g. fromNew Focus Inc., Santa Clara, Calif.) or with a scanning mirror fromGeneral Scanning, Inc., Watertown Mass.

[0204] The additive effect of multiple perforations may be exploitedwith diode lasers. Laser diodes supplied by SDL Corporation (San Jose,Calif.) transmit a continuous beam of from 1.8 to 1.96 micron wavelengthradiant energy. These diodes operate at up to 500 mW output power andmay be coupled to cumulatively produce higher energies useful forstratum corneum ablation. For example, one diode bar may contain tensuch diodes coupled to produce pulsed energy of 5 mJ per millisecond. Ithas been shown that an ablative effect may be seen with as little as 25mJ of energy delivered to a 1 mm diameter spot. Five 5 millisecondpulses or (25) one millisecond pulses from a diode laser of this typewill thus have an ablative effect approximately equivalent to one 25 mJpulse in the same time period.

[0205] The following examples are descriptions of the use of a laser toincrease the permeability of the stratum corneum for the purpose ofdrawing fluids, gases or other biomolecules, as well as forpharmaceutical delivery. These examples are not meant to limit the scopeof the invention, but are merely embodiments.

EXAMPLE 1

[0206] The laser comprises a flashlamp (PSC Lamps, Webster, N.Y.), anEr:YAG crystal (Union Carbide Crystal Products, Washagoul, Wash.),optical-resonator mirrors (CVI Laser Corp., Albuquerque, N.Mex.), aninfrared transmitting lens (Esco Products Inc., Oak Ridge, N.J.), aswell as numerous standard electrical components such as capacitors,resistors, inductors, transistors, diodes, silicon-controlledrectifiers, fuses and switches, which can be purchased from anyelectrical component supply firm, such as Newark Electronics, LittleRock, Ark.

EXAMPLE 2

[0207] An infrared laser radiation pulse was formed using a solid state,pulsed, Er:YAG laser consisting of two flat resonator mirrors, an Er:YAGcrystal as an active medium, a power supply, and a means of focusing thelaser beam. The wavelength of the laser beam was 2.94 microns. Singlepulses were used.

[0208] The operating parameters were as follows: The energy per pulsewas 40, 80 or 120 mJ, with the size of the beam at the focal point being2 mm, creating an energy fluence of 1.27, 2.55 or 3.82 J/cm². The pulsetemporal width was 300 μs, creating an energy fluence rate of 0.42, 0.85or 1.27×10⁴ W/cm².

[0209] Transepidermal water loss (TEWL) measurements were taken of thevolar aspect of the forearms of human volunteers. Subsequently theforearms were positioned at the focal point of the laser, and the laserwas discharged. Subsequent TEWL measurements were collected from theirradiation sites, and from these the measurements of unirradiatedcontrols were subtracted. The results (shown in FIG. 27) show that atpulse energies of 40, 80 and 120 mJ, the barrier function of the stratumcorneum was reduced and the resulting water loss was measured to be 131,892 and 1743 gm/m²/hr respectively. The tape stripe positive control (25pieces of Scotch Transpore tape serially applied and quickly removedfrom a patch of skin) was measured to be 9.0 gm/m²/hr, greater thanuntouched controls; thus the laser is more efficient at reducing thebarrier function of the stratum corneum than tape-stripping.

[0210] Clinical assessment was conducted 24 hours after irradiation.Only a small eschar was apparent on the site lased at high energy, andno edema was present. None of the volunteers experienced irritation orrequired medical treatment.

EXAMPLE 3

[0211] An infrared laser radiation pulse was formed using a solid state,pulsed, Er:YAG laser consisting of two flat resonator mirrors, an Er:YAGcrystal as an active medium, a power supply, and a means of focusing thelaser beam. The wavelength of the laser beam was 2.94 microns. A singlepulse was used.

[0212] The operating parameters were as follows: The energy per pulsewas 60 mJ, with the size of the beam at the focal point being 2 mm,creating an energy fluence of 1.91 J/cm². The pulse temporal width was300 μs, creating an energy fluence rate of 0.64×10⁴ W/cm².

[0213] The volar aspect of the forearm of a volunteer was placed at thefocal point of the laser, and the laser was discharged. After dischargeof the laser, the ablated site was topically administered a 30% liquidlidocaine solution for two minutes. A 26G-0.5 needle was subsequentlyinserted into the laser ablated site with no observable pain.Additionally, after a 6-minute anesthetic treatment, a 22G-1 needle wasfully inserted into the laser ablated site with no observable pain. Thevolunteer experienced no irritation and did not require medicaltreatment.

EXAMPLE 4

[0214] Ablation threshold energy: Normally hydrated (66%) stratumcorneum was sandwiched between two microscope cover slides, and exposedto a single pulse of irradiation from the Er:YAG laser. Evidence ofablation was determined by holding the sample up to a light and seeingwhether any stratum corneum was left at the irradiated site. From thisexperiment, it was determined that the irradiation threshold energy (fora 2 mm irradiation spot) was approximately 90-120 mJ. The threshold willlikely be higher when the stratum corneum is still overlying epidermis,as in normal skin, since it takes energy to remove the stratum corneumfrom the epidermis, to which it is adherent.

EXAMPLE 5

[0215] Differential Scanning Calorimetry (DSC): FIG. 28 shows a DSC scanof normally hydrated (66%) human stratum corneum, and a scan of stratumcorneum irradiated with the Er:YAG laser using a subablative pulseenergy of 60 mJ. Defining the thermal transition peaks at approximately65, 80 and 92° C., we determined the heat of transition (μJ), center ofthe transition (° C.) and the full-width at half-maximum of thetransition (° C.) (FIGS. 29-31). The results shown are on normal 66%hydrated stratum corneum, dehydrated 33% stratum corneum, steam heatedstratum corneum, Er:YAG laser irradiated stratum corneum, or stratumcorneum that was immersed in chloroform-methanol (a lipid solvent), orbeta-mercaptoethanol (a protein denaturant). The effect of laserirradiation on stratum corneum is consistent (depending on whichtransition you look at, 1, 2 or 3) with changes seen due to thermaldamage (i.e. heated with steam), and delipidization. Permeation with(³H₂O) and transepidermal impedance experiments on skin treated the sameway showed that the result of these treatments (heat, solvent ordenaturant) resulted in increased permeation. Thus, the changes inducedin the stratum corneum with these treatments, changes which areconsistent with those seen in laser irradiated stratum corneum, andchanges which do not result in stratum corneum ablation, result inincreased permeation.

EXAMPLE 6

[0216] Fourier Transform Infrared (FTIR) Spectroscopy: FTIR spectroscopywas used to study stratum corneum treated the same way as in the aboveDSC experiments, except the energy used was between 53 and 76 mJ. Thespectra (see, e.g., FIGS. 32-33) show that absorption bands that are dueto water, proteins and lipids change when the stratum corneum isirradiated. Some of these changes are consistent with changes seenduring non-laser treatment of the stratum corneum (e.g. desiccation,thermal damage, lipid solubilization or protein denaturation). Forexample, the Amide I and II bands, which are due to the presence ofproteins (most likely keratin, which makes up the bulk of protein instratum corneum), shift to a larger wavenumber, consistent with theeffect of desiccation alone (in the case of Amide II) or desiccation andbeta-mercaptoethanol treatment (in the case of Amide I) (see, e.g., FIG.34). The CH₂, vibrations (due to bonds in lipids) always shift to asmaller wavenumber indicating that either the intermolecular associationbetween adjacent lipid molecules has been disturbed and/or theenvironment around the lipid molecules has changed in such a way thatthe vibrational behavior of the molecules changes (see, e.g., FIG. 35).

EXAMPLE 7

[0217] Histology: Numerous in vivo experiments have been done on ratsand humans. Usually, the skin is irradiated with the Er:YAG laser and a2 mm spot and with a particular pulse energy, and then the irradiatedsite is biopsied immediately or 24 hours later. Two examples of typicalresults are shown in FIGS. 36 and 37. FIG. 36 shows rat skin irradiatedat 80 mJ, which is an energy sufficient to make the skin permeable (tolidocaine, for instance) and yet does not show any sign of stratumcorneum ablation. FIG. 37 depicts human skin 24 hours after beingirradiated at 80 mJ. In this case, some change in the appearance of thestratum corneum has taken place (perhaps coagulation of some layers ofstratum corneum into a darkly staining single layer), and yet thestratum corneum is still largely intact and is not ablated. Irradiationof human skin, in vivo, and subsequently examined under a dissectionmicroscope, show that at subablative energies (less than about 90-120mJ), the stratum corneum is still present on the skin. The irradiatedstratum corneum appears slightly whitened in vivo, which might beevidence of desiccation or separation of the stratum corneum from theunderlying tissues.

EXAMPLE 8

[0218] One way to quantify the reduction in the barrier function of thestratum corneum is to measure the reduction in the electrical impedanceof the skin as a consequence of laser irradiation. In this experiment,separate 2 mm spots on the volar aspect of the forearm of a humanvolunteer were irradiated with a single pulse of radiant energy from theEr:YAG laser using a range of energies. An ECG electrode was then placedover the irradiated site and an unirradiated site about 20 cm away onthe same forearm. A 100 Hz sine wave of magnitude 1 volt peak-to-peakwas then used to measure the impedance of the skin. The results of aseries of measurements are shown in FIG. 22, which shows that there is adecrease in skin impedance in skin irradiated at energies as low as 10mJ, using the fitted curve to interpolate data.

EXAMPLE 9

[0219] Pieces of human skin were placed in diffusion cells andirradiated with a single pulse of radiant energy produced by an Er:YAGlaser. The spot size was 2 mm and the energy of the pulse was measuredwith a calibrated energy meter. After irradiation, the diffusion cellswere placed in a 37 degrees Celsius heating block. Phosphate bufferedsaline was added to the receptor chamber below the skin and a small stirbar was inserted in the receptor chamber to keep the fluid continuallymixed. Control skin was left unirradiated. Small volumes ofradiolabelled compounds (either corticosterone or DNA) were then addedto the donor chamber and left for 15 minutes before being removed (inthe case of corticosterone) or were left for the entire duration of theexperiment (in the case of the DNA). Samples were then taken from thereceptor chamber at various times after application of the test compoundand measured in a scintillation or gamma counter. The results of thisexperiment are shown in FIGS. 21 and 26. The results illustrate thatenhanced permeation can occur at sub-ablative laser pulse energies (seethe 77 mJ/pulse data for corticosterone). Although, in the case of theDNA experiment the energy used may have been ablative, enhancedpermeation may still occur when lower energies are used.

EXAMPLE 10

[0220] Histology studies on rat and human skin, irradiated either invivo or in vitro, show little or no evidence of ablation when Er:YAGlaser pulse energies less than about 100-200 mJ are used. (See, e.g.,FIG. 25). Repeating this study showed the same results as the previousstudies. An in vitro permeation study using tritiated water (³H₂O)involving human skin lased at energies from 50 mJ (1.6 J/cm²) to 1250 mJ(40 J/cm²) determined (FIGS. 23 and 24) than an increase in permeationwas seen at low energy fluences up to about 5 J/cm², whereupon thepermeation is more-or-less constant. This shows that there has been alased induced enhancement of permeation (of tritiated water) at energiesthat are sub-ablative.

EXAMPLE 11

[0221] The output of the Er:YAG laser was passed through an aperture todefine it's diameter as 2 mm. Human skin, purchased from a skin bank,was positioned in Franz diffusion cells. The receptor chamber of thecell was filled with 0.9% buffered saline. A single pulse, of measuredenergy, was used to irradiate the skin in separate diffusion cells.Control skin was left unirradiated. When the permeation of lidocaine wasto be tested, a 254 mJ pulse was used, and multiple samples wereirradiated. In the case of γ-interferon, a 285 mJ pulse was used, andmultiple samples were irradiated. In the case of insulin, a 274 mJ pulsewas used, and multiple samples were irradiated. In the case ofcortisone, either 77 mJ or 117 mJ was used. After irradiation, astirring magnet was place in the receptor chamber of the diffusion cellsand the cells were placed in a heating block held at 37° C. Theradiolabelled lidocaine, gamma-interferon and insulin were diluted inbuffered saline, and 100 μL of the resulting solutions was placed in thedonor chamber of separate diffusion cells. The donor was left on theskin for the duration of the experiment. At various timespost-drug-application, samples were taken from the receptor chamber andthe amount of drug present was assayed with either a gamma-counter, or aliquid scintillation counter. Graphs of the resulting data are shown inFIGS. 39, 40 and 41. From this, and similar data, the permeabilityconstants were derived and are shown as follows: Drug PermeabilityConstant, k₂ (× 10⁻³ cm/hr) Lidocaine 2.62 +/− 6.9  γ-Interferon 9.74+/− 2.05 Insulin 11.3 +/− 0.93

EXAMPLE 12

[0222] This data was collected during the same experiment as the TEWLresults (see Example 2 and FIG. 27). In the case of the blanching assay,baseline skin color (redness) measurements were then taken of each spotusing a Minolta CR-300 Chromameter (Minolta Inc., NJ). The Er:YAG laserwas then used to ablate six 2 mm spots on one forearm, at energies of40, 80 and 120 mJ. A spot (negative calorimeter control) directlyadjacent to the laser irradiated spots remained untouched. Subsequently,a thin film of 1% hydrocortisone ointment was applied to six of thelased spots on the treatment arm. One untouched spot on thecontralateral arm was administered a thin layer of Diprolene(β-methasone), which is a strong steroid that can permeate the intactstratum corneum in an amount sufficient to cause measurable skinblanching. An occlusive patch, consisting of simple plastic wrap, wasfixed with gauze and dermatological tape over all sites on both arms andleft in place for two hours, after which the administered steroids weregently removed with cotton swabs. Colorimeter measurements were thentaken over every unirradiated and irradiated spot at 2, 4, 8, 10, 12 and26 hours post-irradiation, these results are shown in FIG. 38. Finally,the skin was clinically assessed for evidence of irritation at the 26hour evaluation.

[0223] The results of the chromameter measurements show that someerythema (reddening) of the skin occurred, but because of theopposite-acting blanching permeating hydrocortisone, the reddening wasless than that seen in the control spots which did not receivehydrocortisone. The Diprolene control proved the validity of themeasurements and no problems were seen in the volunteers at the 26 hourevaluation, although in some of the cases the site of irradiation wasapparent as a small red spot.

EXAMPLE 13

[0224] The radiant output of the Er:YAG laser is focussed and collimatedwith optics to produce a spot size at the surface of the skin of, forexample, 5 mm. The skin of the patient, being the site of, or close tothe site of disease, is visually examined for anything that might affectthe pharmacokinetics of the soon to be administered drug (e.g.,significant erythema or a wide-spread loss of the integrity of thestratum corneum). This site, which is to be the site of irradiation, isgently cleansed to remove all debris and any extraneous compounds suchas perfume or a buildup of body oils. A disposable tip attached to thelaser pressed up to the skin prior to irradiation is used to contain anyablated biological debris, as well as to contain any errant radiantenergy produced by the laser. A single laser pulse (approximately 350 μslong), with an energy of 950 mJ, is used to irradiate the spot. Theresult is a reduction or elimination of the barrier function of thestratum corneum. Subsequently, an amount of pharmaceutical,hydrocortisone for example, is spread over the irradiation site. Thepharmaceutical may be in the form of an ointment so that it remains onthe site of irradiation. Optionally, an occlusive patch is placed overthe drug in order to keep it in place over the irradiation site.

EXAMPLE 14

[0225] An infrared laser radiation pulse was formed using a solid state,pulsed, Er:YAG laser consisting of two flat resonator mirrors, an Er:YAGcrystal as an active medium, a power supply, and a means of focusing thelaser beam. The wavelength of the laser beam was 2.94 microns. Theduration of the pulse was approximately 300 μs. The spot size wasapproximately 2 mm, with an energy fluence of 5 J/cm². Single pulseswere used.

[0226] Three 2 mm diameter spots were created on a flaccid penis.Subsequent to ablation a pharmaceutical preparation of alprostadil(Caverject from Pharmacia & Upjohn, Kalamazoo, Minn.) was applied to asmall patch consisting of tissue paper. The patch was applied to themultiple perforated areas of the skin on the then flaccid penis and heldthere with adhesive tape for 45 minutes. After approximately 35 minutes,the patient obtained an erection that was sustained for more than 1hour.

[0227] The benefit of this route of administration is that it ispainless. The normal method of administration of alprostadil involvesinjecting the compound deep into the corpus cavernosum of the penis witha hypodermic needle. Not only is such a procedure painful, but it alsoresults in potentially infectious contaminated sharp.

EXAMPLE 15

[0228] An infrared laser radiation pulse can be formed using a solidstate, pulsed, Er:YAG laser consisting of two flat resonator mirrors, anEr:YAG crystal as an active medium, a power supply, and a means offocusing the laser beam. The wavelength of the laser beam is preferably2.94 microns. The duration of the pulse is preferably approximately 300μs. The spot size is preferably approximately 2 mm, with an impulseenergy of approximately 150 mJ creating an energy fluence ofapproximately 5 J/cm². Single pulses of radiant energy from theTRANSMEDICA™ Er:YAG laser, with the operating parameters describedabove, is preferably used to irradiate 2 mm diameter spots on areas ofthe scalp exhibiting hair loss. Multiple irradiation sites can be used.Subsequent to irradiation, minoxidil (for example Rogaine from Pharmacia& Upjohn, Kalamazoo, Mich.) may be applied to access interstitial spacesin the scalp, allowing greater quantities of the pharmaceutical tostimulate root follicles than is available by transcutaneous absorptionalone. Alternatively, subsequent to ablation, androgen inhibitors may beapplied through the laser ablated sites. These inhibitors act to counterthe effects of androgens in hair loss.

EXAMPLE 16

[0229] Skin resurfacing is a widely used and commonly requested cosmeticprocedure whereby wrinkles are removed from (generally) the face of apatient by ablating approximately the outermost 400 microns of skin withthe radiant energy produced by a laser (Dover J. S., Hruza G. J., “LaserSkin Resurfacing,” Semin. Cutan. Med. Surg., 15(3):177-88, 1996). Aftertreatment, often a “mask” made out of hydrogel (which is a gelatine-likematerial that consists mostly of water) is applied to the irradiatedarea to provide both a feeling of coolness and also to preventundesirable desiccation of the treated skin and “weeping” of bodilyfluids.

[0230] The pain associated with this procedure would be intolerablewithout the use of local or general anesthesia. Generally, multiple(perhaps up to 30) local injections of lidocaine are completed prior tothe irradiation of the skin. These injections themselves take asignificant amount of time to perform and are themselves relativelypainful.

[0231] Single pulses of radiant energy from the TRANSMEDICA™ Er:YAGlaser is preferably used to irradiate 2 mm diameter spots on areas ofthe face required for the multiple applications of lidocaine prior toskin resurfacing. The energy used in each laser pulse is preferably 150mJ. Subsequent to irradiation, lidocaine is applied for generalanesthesia. Furthermore, by incorporating lidocaine (preferably, thehydrophillic version which is lidocaine-HCl) into the hydrogel, or otherpatch or gel means of containment, and applying this complex (in thephysical form of a “face-mask”) to the patient's face prior to the laserirradiation but after ablating the stratum corneum with the Er:YAG laserfrom a matrix of sites throughout the treatment area, sufficientanesthesia will be induced for the procedure to be done painlessly. Itmay also be beneficial to incorporate a sedative within the hydrogel tofurther prepare the patient for what can be a distressing medicalprocedure. Optionally, the “face-mask” can be segmented into severalaesthetic-units suitable for single application to particularlaser-treatment regions of the face. Finally, another “face-mask”incorporating beneficial pharmaceuticals, such as antibiotics (e.g.Bacitracin, Neosporin, Polysporin, and Sulphadene) or long term topicalor systemic analgesics, such as fentanyl or demeral, can be applied tothe patient after skin resurfacing treatment.

EXAMPLE 17

[0232] The growth of hairs in the nose (primarily in men) is a commoncosmetic problem. The current therapy, which involves pulling the hairsout with tweezers, is painful and nonpermanent. An infrared laserradiation pulse can be formed using a solid state, pulsed, Er:YAG laserconsisting of two flat resonator mirrors, an Er:YAG crystal as an activemedium, a power supply, and a means of focusing the laser beam. Thewavelength of the laser beam is preferably 2.94 microns. The duration ofthe pulse approximately is preferably 300 μs. The spot size ispreferably approximately 2 mm, with an impulse energy of approximately150 mJ creating an energy fluence of approximately 5 J/cm².

[0233] Single pulses of radiant energy from the TRANSMEDICA™ Er:YAGlaser is preferably used, with the above described operating parameters,to irradiate 2 mm diameter spots on the nasal mucosa exhibitingcosmetically unappealing hair growth. Multiple irradiation sites can beused. The irradiation by itself can be sufficient to alter the tissuethereby inhibiting subsequent hair growth thus irradiation may be itselfsufficient to alter the tissue, inhibiting subsequent hair growth.Alternatively, subsequent to irradiation, a dye, for example indocyaninegreen, which absorbs different wavelengths of radiation, can be applied.After the dye has been absorbed into the nasal passage, 810 nm radiantenergy from a diode laser (GaAlAs laser) can be used to raise thetemperature of the surrounding tissue. This acts to selectively damagethe hair follicles in contact with the dye. As a result the nasal tissueis modified so that hair growth does not reoccur, or at least does notrecur as quickly as it does after manual hair removal.

[0234] While various applications of this invention have been shown anddescribed, it should be apparent to those skilled in the art that manymodifications of the described techniques are possible without departingfrom the inventive concepts herein.

We claim:
 1. A method for preparing the skin for treatment of cutaneousor subcutaneous compounds, comprising the steps of: a) focusing a laserbeam with sufficient energy fluence to ablate or alter the skin at leastas deep as the stratum corneum, but not as deep as the capillary layer;b) firing the laser to create a site of ablation or alteration, the sitehaving a diameter of between 0.5 microns and 5.0 cm; c) applying a dye,a compound that alters the optical properties of stratum corneum, or acompound that stimulates the body's production of molecules that arestrong absorbers of light; and d) firing a second laser with awavelength that is absorbed by the applied dye, the compound thatstimulates the optical properties of stratum corneum or the compoundthat stimulates the body's production of molecules that are strongabsorbers of light.
 2. The method of claim 1 wherein the laser beam hasa wavelength of 0.2-10 microns
 3. The method of claim 1 wherein thelaser beam has a wavelength of between 1.5-3.0 microns.
 4. The method ofclaim 1 wherein the laser beam has a wavelength of about 2.94 microns.5. The method of claim 1 wherein the laser beam is emitted by a laserselected from the group consisting of continuous wave-lasers Er:YAG,pulsed CO₂, Ho:YAG, Er:YAP, Er/Cr:YSGG, Ho:YSGG, Er:GGSG, Er:YLF,Tm:YAG, Ho:YAG, Ho/Nd:Yalo₃, cobalt:MgF₂, HF chemical, DF chemical,carbon monoxide, deep UV lasers, and frequency tripled Nd:YAG lasers. 6.The method of claim 1 wherein the laser beam is emitted by a modulatedlaser selected from the group consisting of continuous-wave CO₂, Nd:YAG,Thullium:YAG and diode lasers.
 7. The method of claim 1 wherein thelaser beam is emitted by an Er:YAG laser.
 8. The method of claim 1wherein the laser beam is focused at a site on the skin with a diameterof 0.1-5.0 mm.
 9. The method of claim 1 wherein the energy fluence ofthe laser beam at the skin is 0.03-100,000 J/cm².
 10. The method ofclaim 1 wherein the energy fluence of the laser beam at the skin is0.03-9.6 J/cm².
 11. The method of claim 1 wherein the pulse width isbetween 1 femtosecond and 1,000 microseconds.
 12. The method of claim 1wherein the pulse width is between 1 and 1000 microseconds.
 13. Themethod of claim 1 wherein multiple ablations or alterations are made toprepare the skin for dye delivery.
 14. The method of claim 1 furthercomprising a beam splitter positioned to create, simultaneously from thelaser, multiple sites of ablation or alteration.
 15. The method of claim14 wherein the beam splitter is selected from a series of partiallysilvered mirrors, a series of dichroic mirrors, and a series ofbeam-splitting prisms.
 16. The method of claim 14 further comprising ameans to deflect the beam at different angles to create different sitesof ablation alteration on the skin.
 17. The method of claim 14 furthercomprising a means to scan the laser beam to create one continuous pathof ablation or alteration.
 18. The method of claim 1 wherein the dye isused to stain subcutaneous structures.
 19. The method of claim 1 whereinthe dye is indocyanine green.
 20. The method of claim 1 wherein the dyeis specific for lipids, proteins, or carbohydrates.
 21. The method ofclaim 1 wherein the wavelength of the laser beam fired from the secondlaser at the site of dye delivery is about the wavelength of peakabsorption of the dye.
 22. The method of claim 21 wherein the wavelengthof the laser beam is about 810 nm.
 23. The method of claim 1 wherein thewavelength of the laser beam fired from the second laser at the site ofdelivery of the compound that stimulates the body's production ofmolecules that are strong absorbers of light is about the wavelength ofpeak absorption of the compound.
 24. The method of claim 23 wherein thecompound that stimulates the body's production of molecules that arestrong absorbers of light is 5-aminolevulinic acid.
 25. A method forincreasing the diffusion of bodily fluids out of, or compounds into, theskin, comprising the steps of: a) applying a compound or an absorbingmaterial to the targeted tissue; b) focusing a laser beam withsufficient energy fluence to create a pressure gradient within thestratum corneum, in the applied compound, or in the optional absorbingmaterial; and c) firing the laser with at least one short rapid pulse tocreate the pressure gradient.
 26. The method of claim 25 wherein thelaser beam has a wavelength of 0.2-10 microns.
 27. The method of claim25 wherein the laser beam has a wavelength of between 1.5-3.0 microns.28. The method of claim 25 wherein the laser beam has a wavelength ofabout 2.94 microns.
 29. The method of claim 25 wherein the laser beam isemitted by a laser selected from the group consisting of Er:YAG, pulsedCO₂ Ho:YAG, Er:YAP, Er/Cr:YSGG, Ho:YSGG, Er:GGSG, Er:YLF, Tm:YAG,Ho:YAG, Ho/Nd:YalO₃, cobalt:MgF₂, HF chemical, DF chemical, carbonmonoxide, deep UV lasers, and frequency tripled Nd:YAG lasers.
 30. Themethod of claim 25 wherein the laser beam is emitted by an Er:YAG laser.31. The method of claim 25 wherein the laser beam is emitted by amodulated laser selected from the group consisting of continuous-waveCO₂, Nd:YAG, Thallium:YAG and diode lasers.
 32. The method of claim 25wherein the pulse width is between 1 femtosecond and 1,000 microseconds.33. The method of claim 25 wherein the pulse width is between 1 and 1000microseconds.
 34. The method of claim 25 wherein the optional absorbingmaterial is placed on or over the targeted tissue before application ofthe compound or firing the laser.
 35. The method of claim 34 wherein thepressure gradient is created in the optional absorbing material.
 36. Themethod of claim 34 wherein the optional absorbing material is a thinfilms of water.
 37. The method of claim 34 wherein the optionalabsorbing material is a dye or a solution with a dye.
 38. The method ofclaim 25 wherein the compound is applied before firing the laser. 39.The method of claim 25 wherein the pressure gradient is created in thestratum corneum simultaneous with the application of the compound. 40.The method of claim 38 wherein the pressure gradient is created in thecompound.
 41. The method of claim 38 wherein the optional absorbingmaterial is placed on or over the compound before firing the laser. 42.The method of claim 41 wherein the pressure gradient is created in theoptional absorbing material.
 43. The method of claim 41 wherein theoptional absorbing material is a thin film of water.
 44. The method ofclaim 25 wherein multiple pulses are used to create the pressuregradient.
 45. The method of claim 25 wherein the stratum corneum isablated or altered before the pressure gradient is created.
 46. A methodfor increasing the diffusion of bodily fluids out of, or compounds into,the skin, comprising the steps of: a) focusing a laser beam withsufficient energy fluence to create plasma within the stratum corneum orin an optional absorbing material on or over the targeted tissue; b)firing the laser with at least one short rapid pulse to create a site ofplasma, the site having a diameter of between 0.5 microns and 5 mm; andc) removing bodily fluids from the targeted tissue or applying acompound to the targeted tissue.
 47. The method of claim 46 wherein thelaser beam has a wavelength of 0.2-10 microns.
 48. The method of claim46 wherein the laser beam has a wavelength of between 1.5-3.0 microns.49. The method of claim 46 wherein the laser beam has a wavelength ofabout 2.94 microns.
 50. The method of claim 46 wherein the laser beam isemitted by a laser selected from the group consisting of Er:YAG, pulsedCO₂ Ho:YAG, Er:YAP, Er/Cr:YSGG, Ho:YSGG, Er:GGSG, Er:YLF, Tm:YAG,Ho:YAG, Ho/Nd:YalO₃, cobalt:MgF₂, HF chemical, DF chemical, carbonmonoxide, deep UV lasers, and frequency tripled Nd:YAG lasers.
 51. Themethod of claim 46 wherein the laser beam is emitted by an Er:YAG laser.52. The method of claim 46 wherein the laser beam is emitted by amodulated laser selected from the group consisting of continuous-waveCO₂, Nd:YAG, Thallium:YAG and diode lasers.
 53. The method of claim 46wherein the pulse width is between 1 femtosecond and 1,000 microseconds.54. The method of claim 46 wherein the pulse width is between 1 and 1000microseconds.
 55. The method of claim 46 wherein multiple pulses areused to create multiple sites of plasma.
 56. The method of claim 46wherein plasma is created in the stratum corneum.
 57. The method ofclaim 46 wherein the optional absorbing material is placed on or overthe targeted tissue before firing the laser.
 58. The method of claim 57wherein plasma is created in the optional Absorbing material.
 59. Themethod of claim 57 wherein the optional absorbing material is a thinfilm of water.
 60. The method of claim 57 wherein the optional absorbingmaterial is a dye or a solution with a dye.
 61. The method of claim 46wherein the compound is applied before firing the laser.
 62. The methodof claim 61 wherein plasma is created in the applied compound.
 63. Amethod for increasing the diffusion of bodily fluids out of, orcompounds into, the skin, comprising the steps of: a) focusing a laserbeam with sufficient energy fluence to create cavitation bubbles in thestratum corneum, in an applied compound, or in an optional absorbingmaterial; b) firing the laser with at least one short rapid pulse tocreate a site of cavitation bubbles, the site having a diameter ofbetween 0.5 microns and 5 mm; and c) removing bodily fluids from thetargeted tissue or applying a compound to the targeted tissue.
 64. Themethod of claim 63 wherein the laser beam has a wavelength of 0.2-10microns.
 65. The method of claim 63 wherein the laser beam has awavelength of between 1.5-3.0 microns.
 66. The method of claim 63wherein the laser beam has a wavelength of about 2.94 microns.
 67. Themethod of claim 63 wherein the laser beam is emitted by a laser selectedfrom the group consisting of Er:YAG, pulsed CO₂ Ho:YAG, Er:YAP,Er/Cr:YSGG, Ho:YSGG, Er:GGSG, Er:YLF, Tm:YAG, Ho:YAG, Ho/Nd:YalO₃,cobalt:MgF₂, HF chemical, DF chemical, carbon monoxide, deep UV lasers,and frequency tripled Nd:YAG lasers.
 68. The method of claim 63 whereinthe laser beam is emitted by an Er:YAG laser.
 69. The method of claim 63wherein the pulse width is between 1 femtosecond and 1,000 microseconds.70. The method of claim 63 wherein the pulse width is between 1 and 1000microseconds.
 71. The method of claim 63 wherein the laser beam isemitted by a modulated laser selected from the group consisting ofcontinuous-wave CO₂, Nd:YAG, Thallium:YAG and diode lasers.
 72. Themethod of claim 63 wherein multiple pulses are used to create multiplesites of cavitation bubbles.
 73. The method of claim 63 whereincavitation bubbles are created in the stratum corneum before firing thelaser.
 74. The method of claim 63 wherein the optional absorbingmaterial is placed on or over the targeted tissue before firing thelaser.
 75. The method of claim 74 wherein the cavitation bubbles arecreated in the optional absorbing material.
 76. The method of claim 74wherein the optional absorbing material is a thin film of water.
 77. Themethod of claim 74 wherein the optional absorbing material is a dye or asolution with a dye.
 78. The method of claim 63 wherein the compound isapplied before firing the laser.
 79. The method of claim 78 wherein thecavitation bubbles are created in the applied compound.
 80. A laserdevice for ablating or altering skin comprising: a) a lasing elementwhich emits a beam at a wavelength of between 0.2 microns and 10microns; b) a power source; c) a high voltage pulse-forming networklinked to the power source; d) a means for exciting the lasing element,linked to the pulse-forming network; e) a laser cavity; and f) a markingmeans which marks the site of ablation or alteration.
 81. The device ofclaim 80 wherein a disposable safety tip contains a pigment and the siteof ablation or alteration is marked by the pigment.
 82. The device ofclaim 80 wherein a pigment is sprayed at the site of ablation oralteration.
 83. The device of claim 80 wherein the site of ablation oralternation is marked before firing the laser.
 84. The device of claim80 wherein the site of ablation or alteration is marked after firing thelaser.